GLS1 inhibitors for treating disease

ABSTRACT

Methods of inhibition GLS1 activity in a human or animal subject are also provided.

This application is a continuation of U.S. application Ser. No.14/791,186, filed Jul. 2, 2015, which claims the benefit of priority ofU.S. provisional Application No. 62/020,539, filed Jul. 3, 2014, thedisclosure of which is hereby incorporated by reference as if writtenherein in its entirety.

The present disclosure relates to new heterocyclic compounds andcompositions, and their application as pharmaceuticals for the treatmentof disease. Methods of inhibition of GLS1 activity in a human or animalsubject are also provided for the treatment of diseases such as cancer.

Metabolic deregulation is a hallmark of cancer as tumors exhibit anincreased demand for nutrients and macromolecules to fuel their rapidproliferation. Glutamine (Gln), the most abundant amino acid incirculation, plays an essential role in providing cancer cells withbiosynthetic intermediates required to support proliferation andsurvival. Specifically, glutaminolysis, or the enzymatic conversion ofglutamine to glutamate, provides proliferating cancer cells with asource of nitrogen for amino acid and nucleotide synthesis, and a carbonskeleton to fuel ATP and NADPH synthesis through the TCA cycle. Inaddition to supporting cell growth, glutamine metabolism plays acritical role in maintaining cellular redox homeostasis as glutamate canbe converted into glutathione, the major intracellular antioxidant.

Glutaminolysis is regulated by mitochondrial glutaminase (GLS), the ratelimiting enzyme that catalyzes the conversion of Gln to glutamate andammonia. Mammalian cells contain 2 genes that encode glutaminase: thekidney-type (GLS1) and liver-type (GLS2) enzymes. Each has been detectedin multiple tissue types, with GLS1 being widely distributed throughoutthe body. GLS1 is a phosphate-activated enzyme that exists in humans astwo major splice variants, a long form (referred to as KGA) and a shortform (GAC), which differ only in their C-terminal sequences. Both formsof GLS1 are thought to bind to the inner membrane of the mitochondrionin mammalian cells, although at least one report suggests thatglutaminase may exist in the intramembrane space, dissociated from themembrane. GLS is frequently overexpressed in human tumors and has beenshown to be positively regulated by oncogenes such as Myc. Consistentwith the observed dependence of cancer cell lines on glutaminemetabolism, pharmcological inhibition of GLS offers the potential totarget Gln addicted tumors.

Thus, there is a need for glutaminase inhibitors that are specific andcapable of being formulated for in vivo use.

SUMMARY

Accordingly, the inventors herein disclose new compositions and methodsfor inhibiting glutaminase activity.

Provided is a compound of structural Formula I

or a salt thereof, wherein: n is chosen from 3, 4, and 5; each R^(X) andR^(Y) is independently chosen from alkyl, cyano, H, and halo, or twoR^(X) groups together with the atoms to which they are attachedoptionally form a cycloalkyl ring; A¹ is chosen from C and N; A², A³,and A⁴ are independently chosen from N, O, S, and CH, wherein at leastone of A¹, A², A³, and A⁴ is chosen from N, O, and S; R¹ and R² are eachindependently chosen from alkenyl, alkyl, aryl, arylalkyl, cycloalkyl,cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, and heterocycloalkylalkyl, wherein R¹ and R² each maybe optionally substituted with one to three R^(Z) groups, wherein R¹ andR² together with the atoms to which they are attached optionally form anheteroaryl, or heterocycloalkyl ring, which may be optionallysubstituted with one to three R^(Z) groups; R³ is chosen from alkenyl,alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H,halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,heterocycloalkylalkyl, hydroxyl, C(R⁴)₂C(O)R⁴, C(R⁴)₂C(O)N(R⁴)₂,C(R⁴)₂N(R⁴)₂, C(R⁴)₂NR⁴C(O)R⁴, C(R⁴)₂NR⁴C(O)OR⁴, C(R⁴)₂NR⁴C(O)N(R⁴)₂,C(R⁴)₂NR⁴S(O)R⁴, C(R⁴)₂NR⁴S(O)₂R⁴, N(R⁴)₂, NR⁴C(O)R⁴, NR⁴C(O)OR⁴,NR⁴C(O)N(R⁴)₂, NR⁴S(O)R⁴, NR⁴S(O)₂R⁴, C(O)N(R⁴)₂, S(O)N(R⁴)₂,S(O)₂N(R⁴)₂, C(O)R⁴, SR⁴, S(O)R⁴, and S(O)₂R⁴; wherein each R³ may beoptionally substituted with one to three R^(Z) groups; each R⁴ isindependently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl,cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl,wherein each R⁴ may be optionally substituted with one to three R^(Z)groups, wherein two R⁴ groups together with the atoms to which they areattached optionally form an heteroaryl, or heterocycloalkyl ring, whichmay be optionally substituted with one to three R^(Z) groups; each R^(Z)group is independently chosen from alkenyl, alkoxy, alkoxyalkyl,alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl,alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl,alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl,alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl,alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl,aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano,cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylhaloalkyl,cycloalkyloxy, H, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl,haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl,haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl,haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl,haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl,haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl,haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl,haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl,halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy,haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl,haloheterocycloalkylalkyloxy, haloheterocycloalkyloxy, heteroaryl,heteroarylalkyl, heteroarylalkyloxy, heteroarylhaloalkyl, heteroaryloxy,heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy,heterocycloalkylhaloalkyl, heterocycloalkyloxy, hydroxyl, oxo, N(R⁵)₂,NR⁵C(O)R⁵, NR⁵C(O)OR⁵, NR⁵C(O)N(R⁵)₂, NR⁵S(O)R⁵, NR⁵S(O)₂R⁵, C(O)N(R⁵)₂,S(O)N(R⁵)₂, S(O)₂N(R⁵)₂, C(O)R⁵, C(O)OR⁵, SR⁵, S(O)R⁵, and S(O)₂R⁵; eachR⁵ is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl,cyano, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, whereintwo R⁵ groups together with the atoms to which they are attachedoptionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkylring, which may be optionally substituted with one to three R^(X)groups; and Z is a monocyclic heteroaryl, which may be optionallysubstituted.

Provided is a composition comprising a compound of Formula I and apharmaceutically acceptable carrier, adjuvant, or vehicle.

Provided is a method of inhibiting GLS1 activity in a biological samplecomprising contacting the biological sample with a compound of FormulaI.

Provided is a method of treating a GLS1-mediated disorder in a subjectin need thereof, comprising the step of administering to the subject acompound of Formula I.

Provided is a method of treating a GLS1-mediated disorder in a subjectin need thereof, comprising the sequential or co-administration of acompound of Formula I or a pharmaceutically acceptable salt thereof, andanother therapeutic agent.

Provided is a compound of any of Formula I for use in human therapy.

Provided is a compound of any of Formula I for use in treating aGLS1-mediated disease.

Provided is a use of a compound of Formula I for the manufacture of amedicament to treat a GLS1-mediated disease.

DETAILED DESCRIPTION Abbreviations and Definitions

To facilitate understanding of the disclosure, a number of terms andabbreviations as used herein are defined below as follows:

When introducing elements of the present disclosure or the preferredembodiment(s) thereof, the articles “a”, “an”, “the” and “said” areintended to mean that there are one or more of the elements. The terms“comprising”, “including” and “having” are intended to be inclusive andmean that there may be additional elements other than the listedelements.

The term “and/or” when used in a list of two or more items, means thatany one of the listed items can be employed by itself or in combinationwith any one or more of the listed items. For example, the expression “Aand/or B” is intended to mean either or both of A and B, i.e. A alone, Balone or A and B in combination. The expression “A, B and/or C” isintended to mean A alone, B alone, C alone, A and B in combination, Aand C in combination, B and C in combination or A, B, and C incombination.

When ranges of values are disclosed, and the notation “from n₁ . . . ton₂” or “between n₁ . . . and n₂” is used, where n₁ and n₂ are thenumbers, then unless otherwise specified, this notation is intended toinclude the numbers themselves and the range between them. This rangemay be integral or continuous between and including the end values. Byway of example, the range “from 2 to 6 carbons” is intended to includetwo, three, four, five, and six carbons, since carbons come in integerunits. Compare, by way of example, the range “from 1 to 3 μM(micromolar),” which is intended to include 1 μM, 3 μM, and everythingin between to any number of significant figures (e.g., 1.255 μM, 2.1 μM,2.9999 μM, etc.).

The term “about,” as used herein, is intended to qualify the numericalvalues that it modifies, denoting such a value as variable within amargin of error. When no particular margin of error, such as a standarddeviation to a mean value given in a chart or table of data, is recited,the term “about” should be understood to mean that range which wouldencompass the recited value and the range which would be included byrounding up or down to that figure as well, taking into accountsignificant figures.

The term “acyl,” as used herein, alone or in combination, refers to acarbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl,heterocycle, or any other moiety were the atom attached to the carbonylis carbon. An “acetyl” group refers to a —C(O)CH₃ group. An“alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached tothe parent molecular moiety through a carbonyl group. Examples of suchgroups include methylcarbonyl and ethylcarbonyl. Examples of acyl groupsinclude formyl, alkanoyl and aroyl.

The term “alkenyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain hydrocarbon radical having one or moredouble bonds and containing from 2 to 20 carbon atoms. In certainembodiments, the alkenyl will comprise from 2 to 6 carbon atoms. Theterm “alkenylene” refers to a carbon-carbon double bond system attachedat two or more positions such as ethenylene [(—CH═CH—), (—C::C—)].Examples of suitable alkenyl radicals include ethenyl, propenyl,2-methylpropenyl, 1,4-butadienyl and the like. Unless otherwisespecified, the term “alkenyl” may include “alkenylene” groups.

The term “alkoxy,” as used herein, alone or in combination, refers to analkyl ether radical, wherein the term alkyl is as defined below.Examples of suitable alkyl ether radicals include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,and the like.

The term “alkyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain alkyl radical containing from 1 to 20carbon atoms. In certain embodiments, the alkyl will comprise from 1 to10 carbon atoms. In further embodiments, the alkyl will comprise from 1to 6 carbon atoms. Alkyl groups may be optionally substituted as definedherein. Examples of alkyl radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,hexyl, octyl, noyl and the like. The term “alkylene,” as used herein,alone or in combination, refers to a saturated aliphatic group derivedfrom a straight or branched chain saturated hydrocarbon attached at twoor more positions, such as methylene (—CH₂—). Unless otherwisespecified, the term “alkyl” may include “alkylene” groups.

The term “alkylamino,” as used herein, alone or in combination, refersto an alkyl group attached to the parent molecular moiety through anamino group. Suitable alkylamino groups may be mono- or dialkylated,forming groups such as, for example, N-methylamino, N-ethylamino,N,N-dimethylamino, N,N-ethylmethylamino and the like.

The term “alkylidene,” as used herein, alone or in combination, refersto an alkenyl group in which one carbon atom of the carbon-carbon doublebond belongs to the moiety to which the alkenyl group is attached.

The term “alkylthio,” as used herein, alone or in combination, refers toan alkyl thioether (R—S—) radical wherein the term alkyl is as definedabove and wherein the sulfur may be singly or doubly oxidized. Examplesof suitable alkyl thioether radicals include methylthio, ethylthio,n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio,tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

The term “alkynyl,” as used herein, alone or in combination, refers to astraight-chain or branched chain hydrocarbon radical having one or moretriple bonds and containing from 2 to 20 carbon atoms. In certainembodiments, the alkynyl comprises from 2 to 6 carbon atoms. In furtherembodiments, the alkynyl comprises from 2 to 4 carbon atoms. The term“alkynylene” refers to a carbon-carbon triple bond attached at twopositions such as ethynylene (—C:::C—, —C≡C—). Examples of alkynylradicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl,butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like.Unless otherwise specified, the term “alkynyl” may include “alkynylene”groups.

The terms “amido” and “carbamoyl” as used herein, alone or incombination, refer to an amino group as described below attached to theparent molecular moiety through a carbonyl group, or vice versa. Theterm “C-amido” as used herein, alone or in combination, refers to a—C(O)N(RR′) group with R and R′ as defined herein or as defined by thespecifically enumerated “R” groups designated. The term “N-amido” asused herein, alone or in combination, refers to a RC(O)N(R′)— group,with R and R′ as defined herein or as defined by the specificallyenumerated “R” groups designated. The term “acylamino” as used herein,alone or in combination, embraces an acyl group attached to the parentmoiety through an amino group. An example of an “acylamino” group isacetylamino (CH₃C(O)NH—).

The term “amino,” as used herein, alone or in combination, refers to—NRR′, wherein R and R′ are independently selected from the groupconsisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl,heteroaryl, and heterocycloalkyl, any of which may themselves beoptionally substituted. Additionally, R and R′ may combine to formheterocycloalkyl, either of which may be optionally substituted.

The term “aryl,” as used herein, alone or in combination, means acarbocyclic aromatic system containing one, two or three rings whereinsuch polycyclic ring systems are fused together. The term “aryl”embraces aromatic groups such as phenyl, naphthyl, anthracenyl, andphenanthryl.

The term “arylalkenyl” or “aralkenyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkenyl group.

The term “arylalkoxy” or “aralkoxy,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkoxy group.

The term “arylalkyl” or “aralkyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkyl group.

The term “arylalkynyl” or “aralkynyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkynyl group.

The term “arylalkanoyl” or “aralkanoyl” or “aroyl,” as used herein,alone or in combination, refers to an acyl radical derived from anaryl-substituted alkanecarboxylic acid such as benzoyl, napthoyl,phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl,(2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

The term aryloxy as used herein, alone or in combination, refers to anaryl group attached to the parent molecular moiety through an oxy.

The terms “benzo” and “benz,” as used herein, alone or in combination,refer to the divalent radical C₆H₄=derived from benzene. Examplesinclude benzothiophene and benzimidazole.

The term “carbamate,” as used herein, alone or in combination, refers toan ester of carbamic acid (—NHCOO—) which may be attached to the parentmolecular moiety from either the nitrogen or acid end, and which may beoptionally substituted as defined herein.

The term “O-carbamyl” as used herein, alone or in combination, refers toa —OC(O)NRR′, group—with R and R′ as defined herein.

The term “N-carbamyl” as used herein, alone or in combination, refers toa ROC(O)NR′— group, with R and R′ as defined herein.

The term “carbonyl,” as used herein, when alone includes formyl [—C(O)H]and in combination is a —C(O)— group.

The term “carboxyl” or “carboxy,” as used herein, refers to —C(O)OH orthe corresponding “carboxylate” anion, such as is in a carboxylic acidsalt. An “O-carboxy” group refers to a RC(O)O— group, where R is asdefined herein. A “C-carboxy” group refers to a —C(O)OR groups where Ris as defined herein.

The term “cyano,” as used herein, alone or in combination, refers to—CN.

The term “cycloalkyl,” or, alternatively, “carbocycle,” as used herein,alone or in combination, refers to a saturated or partially saturatedmonocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moietycontains from 3 to 12 carbon atom ring members and which may optionallybe a benzo fused ring system which is optionally substituted as definedherein. In certain embodiments, the cycloalkyl will comprise from 5 to 7carbon atoms. Examples of such cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronapthyl,indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and thelike. “Bicyclic” and “tricyclic” as used herein are intended to includeboth fused ring systems, such as decahydronaphthalene,octahydronaphthalene as well as the multicyclic (multicentered)saturated or partially unsaturated type. The latter type of isomer isexemplified in general by, bicyclo[1,1,1]pentane, camphor, adamantane,and bicyclo[3,2,1]octane.

The term “ester,” as used herein, alone or in combination, refers to acarboxy group bridging two moieties linked at carbon atoms.

The term “ether,” as used herein, alone or in combination, refers to anoxy group bridging two moieties linked at carbon atoms.

The term “halo,” or “halogen,” as used herein, alone or in combination,refers to fluorine, chlorine, bromine, or iodine.

The term “haloalkoxy,” as used herein, alone or in combination, refersto a haloalkyl group attached to the parent molecular moiety through anoxygen atom.

The term “haloalkyl,” as used herein, alone or in combination, refers toan alkyl radical having the meaning as defined above wherein one or morehydrogens are replaced with a halogen. Specifically embraced aremonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkylradical, for one example, may have an iodo, bromo, chloro or fluoro atomwithin the radical. Dihalo and polyhaloalkyl radicals may have two ormore of the same halo atoms or a combination of different halo radicals.Examples of haloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. “Haloalkylene” refers to a haloalkyl group attached attwo or more positions. Examples include fluoromethylene (—CFH—),difluoromethylene (—CF₂—), chloromethylene (—CHCl—) and the like.

The term “heteroalkyl,” as used herein, alone or in combination, refersto a stable straight or branched chain, or cyclic hydrocarbon radical,or combinations thereof, fully saturated or containing from 1 to 3degrees of unsaturation, consisting of the stated number of carbon atomsand from one to three heteroatoms selected from the group consisting ofO, N, and S, and wherein the nitrogen and sulfur atoms may optionally beoxidized and the nitrogen heteroatom may optionally be quaternized. Theheteroatom(s) O, N and S may be placed at any interior position of theheteroalkyl group. Up to two heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃.

The term “heteroaryl,” as used herein, alone or in combination, refersto a 3 to 15 membered unsaturated heteromonocyclic ring, or a fusedmonocyclic, bicyclic, or tricyclic ring system in which at least one ofthe fused rings is aromatic, which contains at least one atom selectedfrom the group consisting of O, S, and N. In certain embodiments, theheteroaryl will comprise from 5 to 7 carbon atoms. The term alsoembraces fused polycyclic groups wherein heterocyclic rings are fusedwith aryl rings, wherein heteroaryl rings are fused with otherheteroaryl rings, wherein heteroaryl rings are fused withheterocycloalkyl rings, or wherein heteroaryl rings are fused withcycloalkyl rings. Examples of heteroaryl groups include pyrrolyl,pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl,oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl,indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl,quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl,benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl,benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl,tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl,thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Exemplarytricyclic heterocyclic groups include carbazolyl, benzidolyl,phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyland the like.

The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” asused herein, alone or in combination, each refer to a saturated,partially unsaturated, or fully unsaturated monocyclic, bicyclic, ortricyclic heterocyclic group containing at least one heteroatom as aring member, wherein each the heteroatom may be independently selectedfrom the group consisting of nitrogen, oxygen, and sulfur In certainembodiments, the hetercycloalkyl will comprise from 1 to 4 heteroatomsas ring members. In further embodiments, the hetercycloalkyl willcomprise from 1 to 2 heteroatoms as ring members. In certainembodiments, the hetercycloalkyl will comprise from 3 to 8 ring membersin each ring. In further embodiments, the hetercycloalkyl will comprisefrom 3 to 7 ring members in each ring. In yet further embodiments, thehetercycloalkyl will comprise from 5 to 6 ring members in each ring.“Heterocycloalkyl” and “heterocycle” are intended to include sulfones,sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclicfused and benzo fused ring systems; additionally, both terms alsoinclude systems where a heterocycle ring is fused to an aryl group, asdefined herein, or an additional heterocycle group. Examples ofheterocycle groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl,dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl,dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl,benzothiazolyl, dihydroindolyl, dihy-dropyridinyl, 1,3-dioxanyl,1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl,pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and thelike. The heterocycle groups may be optionally substituted unlessspecifically prohibited.

The term “hydrazinyl” as used herein, alone or in combination, refers totwo amino groups joined by a single bond, i.e., —N—N—.

The term “hydroxy,” as used herein, alone or in combination, refers to—OH.

The term “hydroxyalkyl,” as used herein, alone or in combination, refersto a hydroxy group attached to the parent molecular moiety through analkyl group.

The term “imino,” as used herein, alone or in combination, refers to═N—.

The term “iminohydroxy,” as used herein, alone or in combination, refersto ═N(OH) and ═N—O—.

The phrase “in the main chain” refers to the longest contiguous oradjacent chain of carbon atoms starting at the point of attachment of agroup to the compounds of any one of the formulas disclosed herein.

The term “isocyanato” refers to a —NCO group.

The term “isothiocyanato” refers to a —NCS group.

The phrase “linear chain of atoms” refers to the longest straight chainof atoms independently selected from carbon, nitrogen, oxygen andsulfur.

The term “lower,” as used herein, alone or in a combination, where nototherwise specifically defined, means containing from 1 to and including6 carbon atoms.

The term “lower aryl,” as used herein, alone or in combination, meansphenyl or naphthyl, either of which may be optionally substituted asprovided.

The term “lower heteroaryl,” as used herein, alone or in combination,means either 1) monocyclic heteroaryl comprising five or six ringmembers, of which between one and four the members may be heteroatomsselected from the group consisting of O, S, and N, or 2) bicyclicheteroaryl, wherein each of the fused rings comprises five or six ringmembers, comprising between them one to four heteroatoms selected fromthe group consisting of O, S, and N.

The term “lower cycloalkyl,” as used herein, alone or in combination,means a monocyclic cycloalkyl having between three and six ring members.Lower cycloalkyls may be unsaturated. Examples of lower cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term “lower heterocycloalkyl,” as used herein, alone or incombination, means a monocyclic heterocycloalkyl having between threeand six ring members, of which between one and four may be heteroatomsselected from the group consisting of O, S, and N. Examples of lowerheterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl,piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyls maybe unsaturated.

The term “lower amino,” as used herein, alone or in combination, refersto —NRR′, wherein R and R′ are independently selected from the groupconsisting of hydrogen, lower alkyl, and lower heteroalkyl, any of whichmay be optionally substituted. Additionally, the R and R′ of a loweramino group may combine to form a five- or six-memberedheterocycloalkyl, either of which may be optionally substituted.

The term “mercaptyl” as used herein, alone or in combination, refers toan RS— group, where R is as defined herein.

The term “nitro,” as used herein, alone or in combination, refers to—NO₂.

The terms “oxy” or “oxa,” as used herein, alone or in combination, referto —O—.

The term “oxo,” as used herein, alone or in combination, refers to ═O.

The term “perhaloalkoxy” refers to an alkoxy group where all of thehydrogen atoms are replaced by halogen atoms.

The term “perhaloalkyl” as used herein, alone or in combination, refersto an alkyl group where all of the hydrogen atoms are replaced byhalogen atoms.

The terms “sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein,alone or in combination, refer the —SO₃H group and its anion as thesulfonic acid is used in salt formation.

The term “sulfanyl,” as used herein, alone or in combination, refers to—S—.

The term “sulfinyl,” as used herein, alone or in combination, refers to—S(O)—.

The term “sulfonyl,” as used herein, alone or in combination, refers to—S(O)₂—.

The term “N-sulfonamido” refers to a RS(═O)₂NR′— group with R and R′ asdefined herein.

The term “S-sulfonamido” refers to a —S(═O)₂NRR′, group, with R and R′as defined herein.

The terms “thia” and “thio,” as used herein, alone or in combination,refer to a —S— group or an ether wherein the oxygen is replaced withsulfur. The oxidized derivatives of the thio group, namely sulfinyl andsulfonyl, are included in the definition of thia and thio.

The term “thiol,” as used herein, alone or in combination, refers to an—SH group.

The term “thiocarbonyl,” as used herein, when alone includes thioformyl—C(S)H and in combination is a —C(S)— group.

The term “N-thiocarbamyl” refers to an ROC(S)NR′— group, with R and R′as defined herein.

The term “O-thiocarbamyl” refers to a —OC(S)NRR′, group with R and R′ asdefined herein.

The term “thiocyanato” refers to a —CNS group.

The term “trihalomethanesulfonamido” refers to a X₃CS(O)₂NR— group withX is a halogen and R as defined herein.

The term “trihalomethanesulfonyl” refers to a X₃CS(O)₂— group where X isa halogen.

The term “trihalomethoxy” refers to a X₃CO— group where X is a halogen.

The term “trisubstituted silyl,” as used herein, alone or incombination, refers to a silicone group substituted at its three freevalences with groups as listed herein under the definition ofsubstituted amino. Examples include trimethysilyl,tert-butyldimethylsilyl, triphenylsilyl and the like.

Any definition herein may be used in combination with any otherdefinition to describe a composite structural group. By convention, thetrailing element of any such definition is that which attaches to theparent moiety. For example, the composite group alkylamido wouldrepresent an alkyl group attached to the parent molecule through anamido group, and the term alkoxyalkyl would represent an alkoxy groupattached to the parent molecule through an alkyl group.

When a group is defined to be “null,” what is meant is that the group isabsent.

The term “optionally substituted” means the anteceding group may besubstituted or unsubstituted. When substituted, the substituents of an“optionally substituted” group may include, without limitation, one ormore substituents independently selected from the following groups or aparticular designated set of groups, alone or in combination: loweralkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl,lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lowerhaloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl,phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, loweracyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester,lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, loweralkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lowerhaloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonicacid, trisubstituted silyl, N₃, SH, SCH₃, C(O)CH₃, CO₂CH₃, CO₂H,pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Twosubstituents may be joined together to form a fused five-, six-, orseven-membered carbocyclic or heterocyclic ring consisting of zero tothree heteroatoms, for example forming methylenedioxy or ethylenedioxy.An optionally substituted group may be unsubstituted (e.g., —CH₂CH₃),fully substituted (e.g., —CF₂CF₃), monosubstituted (e.g., —CH₂CH₂F) orsubstituted at a level anywhere in-between fully substituted andmonosubstituted (e.g., —CH₂CF₃). Where substituents are recited withoutqualification as to substitution, both substituted and unsubstitutedforms are encompassed. Where a substituent is qualified as“substituted,” the substituted form is specifically intended.Additionally, different sets of optional substituents to a particularmoiety may be defined as needed; in these cases, the optionalsubstitution will be as defined, often immediately following the phrase,“optionally substituted with.”

The term R or the term R′, appearing by itself and without a numberdesignation, unless otherwise defined, refers to a moiety selected fromthe group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl,heteroaryl and heterocycloalkyl, any of which may be optionallysubstituted. Such R and R′ groups should be understood to be optionallysubstituted as defined herein. Whether an R group has a numberdesignation or not, every R group, including R, R′ and Rn where n=(1, 2,3, . . . n), every substituent, and every term should be understood tobe independent of every other in terms of selection from a group. Shouldany variable, substituent, or term (e.g. aryl, heterocycle, R, etc.)occur more than one time in a formula or generic structure, itsdefinition at each occurrence is independent of the definition at everyother occurrence. Those of skill in the art will further recognize thatcertain groups may be attached to a parent molecule or may occupy aposition in a chain of elements from either end as written. Thus, by wayof example only, an unsymmetrical group such as —C(O)N(R)— may beattached to the parent moiety at either the carbon or the nitrogen.

Asymmetric centers exist in the compounds disclosed herein. Thesecenters are designated by the symbols “R” or “S,” depending on theconfiguration of substituents around the chiral carbon atom. It shouldbe understood that the disclosure encompasses all stereochemicalisomeric forms, including diastereomeric, enantiomeric, and epimericforms, as well as d-isomers and 1-isomers, and mixtures thereof.Individual stereoisomers of compounds can be prepared synthetically fromcommercially available starting materials which contain chiral centersor by preparation of mixtures of enantiomeric products followed byseparation such as conversion to a mixture of diastereomers followed byseparation or recrystallization, chromatographic techniques, directseparation of enantiomers on chiral chromatographic columns, or anyother appropriate method known in the art. Starting compounds ofparticular stereochemistry are either commercially available or can bemade and resolved by techniques known in the art. Additionally, thecompounds disclosed herein may exist as geometric isomers. The presentdisclosure includes all cis, trans, syn, anti, entgegen (E), andzusammen (Z) isomers as well as the appropriate mixtures thereof.Additionally, compounds may exist as tautomers; all tautomeric isomersare provided by this disclosure. Additionally, the compounds disclosedherein can exist in unsolvated as well as solvated forms withpharmaceutically acceptable solvents such as water, ethanol, and thelike. In general, the solvated forms are considered equivalent to theunsolvated forms.

The term “bond” refers to a covalent linkage between two atoms, or twomoieties when the atoms joined by the bond are considered part of largersubstructure. A bond may be single, double, or triple unless otherwisespecified. A dashed line between two atoms in a drawing of a moleculeindicates that an additional bond may be present or absent at thatposition.

The term “disease” as used herein is intended to be generallysynonymous, and is used interchangeably with, the terms “disorder,”“syndrome,” and “condition” (as in medical condition), in that allreflect an abnormal condition of the human or animal body or of one ofits parts that impairs normal functioning, is typically manifested bydistinguishing signs and symptoms, and causes the human or animal tohave a reduced duration or quality of life.

The term “combination therapy” means the administration of two or moretherapeutic agents to treat a therapeutic condition or disorderdescribed in the present disclosure. Such administration encompassesco-administration of these therapeutic agents in a substantiallysimultaneous manner, such as in a single capsule having a fixed ratio ofactive ingredients or in multiple, separate capsules for each activeingredient. In addition, such administration also encompasses use ofeach type of therapeutic agent in a sequential manner. In either case,the treatment regimen will provide beneficial effects of the drugcombination in treating the conditions or disorders described herein.

GLS1 inhibitor is used herein to refer to a compound that exhibits anIC50 with respect to GLS1 activity of no more than about 100 μM and moretypically not more than about 50 μM, as measured in the GLS1 enzymeassay described generally herein below. IC50 is that concentration ofinhibitor that reduces the activity of an enzyme (e.g., GLS1) tohalf-maximal level. Certain compounds disclosed herein have beendiscovered to exhibit inhibition against GLS1. In certain embodiments,compounds will exhibit an IC50 with respect to GLS1 of no more thanabout 10 μM; in further embodiments, compounds will exhibit an IC50 withrespect to GLS1 of no more than about 5 μM; in yet further embodiments,compounds will exhibit an IC50 with respect to GLS1 of not more thanabout 1 μM; in yet further embodiments, compounds will exhibit an IC50with respect to GLS1 of not more than about 200 nM, as measured in theGLS1 binding assay described herein.

The phrase “therapeutically effective” is intended to qualify the amountof active ingredients used in the treatment of a disease or disorder oron the effecting of a clinical endpoint.

The term “therapeutically acceptable” refers to those compounds (orsalts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitablefor use in contact with the tissues of patients without undue toxicity,irritation, and allergic response, are commensurate with a reasonablebenefit/risk ratio, and are effective for their intended use.

As used herein, reference to “treatment” of a patient is intended toinclude prophylaxis. Treatment may also be preemptive in nature, i.e.,it may include prevention of disease. Prevention of a disease mayinvolve complete protection from disease, for example as in the case ofprevention of infection with a pathogen, or may involve prevention ofdisease progression. For example, prevention of a disease may not meancomplete foreclosure of any effect related to the diseases at any level,but instead may mean prevention of the symptoms of a disease to aclinically significant or detectable level. Prevention of diseases mayalso mean prevention of progression of a disease to a later stage of thedisease.

The term “patient” is generally synonymous with the term “subject” andincludes all mammals including humans. Examples of patients includehumans, livestock (farm animals) such as cows, goats, sheep, pigs, andrabbits, and companion animals such as dogs, cats, rabbits, and horses.Preferably, the patient is a human.

The term “prodrug” refers to a compound that is made more active invivo. Certain compounds disclosed herein may also exist as prodrugs, asdescribed in Hydrolysis in Drug and Prodrug Metabolism: Chemistry,Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M.Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compoundsdescribed herein are structurally modified forms of the compound thatreadily undergo chemical changes under physiological conditions toprovide the compound. Additionally, prodrugs can be converted to thecompound by chemical or biochemical methods in an ex vivo environment.For example, prodrugs can be slowly converted to a compound when placedin a transdermal patch reservoir with a suitable enzyme or chemicalreagent. Prodrugs are often useful because, in some situations, they maybe easier to administer than the compound, or parent drug. They may, forinstance, be bioavailable by oral administration whereas the parent drugis not. The prodrug may also have improved solubility in pharmaceuticalcompositions over the parent drug. A wide variety of prodrug derivativesare known in the art, such as those that rely on hydrolytic cleavage oroxidative activation of the prodrug. An example, without limitation, ofa prodrug would be a compound which is administered as an ester (the“prodrug”), but then is metabolically hydrolyzed to the carboxylic acid,the active entity. Additional examples include peptidyl derivatives of acompound.

The compounds disclosed herein can exist as therapeutically acceptablesalts. The present disclosure includes compounds listed above in theform of salts, including acid addition salts. Suitable salts includethose formed with both organic and inorganic acids. Such acid additionsalts will normally be pharmaceutically acceptable. However, salts ofnon-pharmaceutically acceptable salts may be of utility in thepreparation and purification of the compound in question. Basic additionsalts may also be formed and be pharmaceutically acceptable. For a morecomplete discussion of the preparation and selection of salts, refer toPharmaceutical Salts: Properties, Selection, and Use (Stahl, P.Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

The term “therapeutically acceptable salt,” as used herein, representssalts or zwitterionic forms of the compounds disclosed herein which arewater or oil-soluble or dispersible and therapeutically acceptable asdefined herein. The salts can be prepared during the final isolation andpurification of the compounds or separately by reacting the appropriatecompound in the form of the free base with a suitable acid.Representative acid addition salts include acetate, adipate, alginate,L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate),bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate,formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate),lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate,methanesulfonate, naphthylenesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,3-phenylproprionate, phosphonate, picrate, pivalate, propionate,pyroglutamate, succinate, sulfonate, tartrate, L-tartrate,trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate,para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groupsin the compounds disclosed herein can be quaternized with methyl, ethyl,propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl,dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and sterylchlorides, bromides, and iodides; and benzyl and phenethyl bromides.Examples of acids which can be employed to form therapeuticallyacceptable addition salts include inorganic acids such as hydrochloric,hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic,maleic, succinic, and citric. Salts can also be formed by coordinationof the compounds with an alkali metal or alkaline earth ion. Hence, thepresent disclosure contemplates sodium, potassium, magnesium, andcalcium salts of the compounds disclosed herein, and the like.

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reacting a carboxy group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of therapeutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic quaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, and N,N′-dibenzylethylenediamine. Other representativeorganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, andpiperazine.

A salt of a compound can be made by reacting the appropriate compound inthe form of the free base with the appropriate acid.

Compounds

The present disclosure provides a compound of structural Formula I

or a salt thereof, wherein: n is chosen from 3, 4, and 5; each R^(X) andR^(Y) is independently chosen from alkyl, cyano, H, and halo, or twoR^(X) groups together with the atoms to which they are attachedoptionally form a cycloalkyl ring; A¹ is chosen from C and N; A², A³,and A⁴ are independently chosen from N, O, S, and CH, wherein at leastone of A¹, A², A³, and A⁴ is chosen from N, O, and S; R¹ and R² are eachindependently chosen from alkenyl, alkyl, aryl, arylalkyl, cycloalkyl,cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, and heterocycloalkylalkyl, wherein R¹ and R² each maybe optionally substituted with one to three R^(Z) groups, wherein R¹ andR² together with the atoms to which they are attached optionally form anheteroaryl, or heterocycloalkyl ring, which may be optionallysubstituted with one to three R^(Z) groups; R³ is chosen from alkenyl,alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H,halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,heterocycloalkylalkyl, hydroxyl, C(R⁴)₂C(O)R⁴, C(R⁴)₂C(O)N(R⁴)₂,C(R⁴)₂N(R⁴)₂, C(R⁴)₂NR⁴C(O)R⁴, C(R⁴)₂NR⁴C(O)OR⁴, C(R⁴)₂NR⁴C(O)N(R⁴)₂,C(R⁴)₂NR⁴S(O)R⁴, C(R⁴)₂NR⁴S(O)₂R⁴, N(R⁴)₂, NR⁴C(O)R⁴, NR⁴C(O)OR⁴,NR⁴C(O)N(R⁴)₂, NR⁴S(O)R⁴, NR⁴S(O)₂R⁴, C(O)N(R⁴)₂, S(O)N(R⁴)₂,S(O)₂N(R⁴)₂, C(O)R⁴, SR⁴, S(O)R⁴, and S(O)₂R⁴; wherein each R³ may beoptionally substituted with one to three R^(Z) groups; each R⁴ isindependently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl,cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl,wherein each R⁴ may be optionally substituted with one to three R^(Z)groups, wherein two R⁴ groups together with the atoms to which they areattached optionally form an heteroaryl, or heterocycloalkyl ring, whichmay be optionally substituted with one to three R^(Z) groups; each R^(Z)group is independently chosen from alkenyl, alkoxy, alkoxyalkyl,alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl,alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl,alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl,alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl,alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl,aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano,cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylhaloalkyl,cycloalkyloxy, H, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl,haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl,haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl,haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl,haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl,haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl,haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl,haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl,halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy,haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl,haloheterocycloalkylalkyloxy, haloheterocycloalkyloxy, heteroaryl,heteroarylalkyl, heteroarylalkyloxy, heteroarylhaloalkyl, heteroaryloxy,heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy,heterocycloalkylhaloalkyl, heterocycloalkyloxy, hydroxyl, oxo, N(R⁵)₂,NR⁵C(O)R⁵, NR⁵C(O)OR⁵, NR⁵C(O)N(R⁵)₂, NR⁵S(O)R⁵, NR⁵S(O)₂R⁵, C(O)N(R⁵)₂,S(O)N(R⁵)₂, S(O)₂N(R⁵)₂, C(O)R⁵, C(O)OR⁵, SR⁵, S(O)R⁵, and S(O)₂R⁵; eachR⁵ is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl,cyano, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, whereintwo R⁵ groups together with the atoms to which they are attachedoptionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkylring, which may be optionally substituted with one to three R^(X)groups; and Z is a monocyclic heteroaryl, which may be optionallysubstituted.

In some embodiments, the compound, or a pharmaceutically acceptable saltthereof, has Formula II

or a salt thereof, wherein: n is chosen from 3, 4, and 5; each R^(X) andR^(Y) is independently chosen from alkyl, cyano, H, and halo, or twoR^(X) groups together with the atoms to which they are attachedoptionally form a cycloalkyl ring; A¹ and Z¹ are independently chosenfrom C and N; A², A³, A⁴, Z², Z³, and Z⁴ are independently chosen fromN, O, S, and CH, wherein at least one of A¹, A², A³, and A⁴ and at leastone of Z¹, Z², Z³, and Z⁴ is chosen from N, O, and S; R¹ and R² are eachindependently chosen from alkenyl, alkyl, aryl, arylalkyl, cycloalkyl,cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, and heterocycloalkylalkyl, wherein R¹ and R² each maybe optionally substituted with one to three R^(Z) groups, wherein R¹ andR² together with the atoms to which they are attached optionally form anheteroaryl, or heterocycloalkyl ring, which may be optionallysubstituted with one to three R^(Z) groups; R³ is chosen from alkenyl,alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H,halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,heterocycloalkylalkyl, hydroxyl, C(R⁴)₂C(O)R⁴, C(R⁴)₂C(O)N(R⁴)₂,C(R⁴)₂N(R⁴)₂, C(R⁴)₂NR⁴C(O)R⁴, C(R⁴)₂NR⁴C(O)OR⁴, C(R⁴)₂NR⁴C(O)N(R⁴)₂,C(R⁴)₂NR⁴S(O)R⁴, C(R⁴)₂NR⁴S(O)₂R⁴, N(R⁴)₂, NR⁴C(O)R⁴, NR⁴C(O)OR⁴,NR⁴C(O)N(R⁴)₂, NR⁴S(O)R⁴, NR⁴S(O)₂R⁴, C(O)N(R⁴)₂, S(O)N(R⁴)₂,S(O)₂N(R⁴)₂, C(O)R⁴, SR⁴, S(O)R⁴, and S(O)₂R⁴; wherein each R³ may beoptionally substituted with one to three R^(Z) groups; each R⁴ isindependently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl,cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl,wherein each R⁴ may be optionally substituted with one to three R^(Z)groups, wherein two R⁴ groups together with the atoms to which they areattached optionally form an heteroaryl, or heterocycloalkyl ring, whichmay be optionally substituted with one to three R^(Z) groups; each R^(Z)group is independently chosen from alkenyl, alkoxy, alkoxyalkyl,alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl,alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl,alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl,alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl,alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl,aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano,cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylhaloalkyl,cycloalkyloxy, H, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl,haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl,haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl,haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl,haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl,haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl,haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl,haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl,halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy,haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl,haloheterocycloalkylalkyloxy, haloheterocycloalkyloxy, heteroaryl,heteroarylalkyl, heteroarylalkyloxy, heteroarylhaloalkyl, heteroaryloxy,heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy,heterocycloalkylhaloalkyl, heterocycloalkyloxy, hydroxyl, oxo, N(R⁵)₂,NR⁵C(O)R⁵, NR⁵C(O)OR⁵, NR⁵C(O)N(R⁵)₂, NR⁵S(O)R⁵, NR⁵S(O)₂R⁵, C(O)N(R⁵)₂,S(O)N(R⁵)₂, S(O)₂N(R⁵)₂, C(O)R⁵, C(O)OR⁵, SR⁵, S(O)R⁵, and S(O)₂R⁵; eachR⁵ is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl,cyano, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, whereintwo R⁵ groups together with the atoms to which they are attachedoptionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkylring, which may be optionally substituted with one to three R^(X)groups.

In certain embodiments A¹, A², and A³ are N; and A⁴ is CH.

In certain embodiments A¹ is C; A² and A³ are N; and A⁴ is S.

In certain embodiments Z¹, Z², and Z³ are N; Z⁴ is CH; and R³ is chosenfrom N(R⁴)₂, NR⁴C(O)R⁴, NR⁴C(O)R⁴, and NR⁴C(O)N(R⁴)₂.

In certain embodiments Z¹, Z², and Z³ are N; Z⁴ is CH; and R³ is chosenfrom C(O)N(R⁴)₂, S(O)N(R⁴)₂, S(O)₂N(R⁴)₂, C(O)R⁴, C(O)OR⁴.

In certain embodiments Z¹ is C; Z² and Z³ are N; Z⁴ is S; and R³ ischosen from N(R⁴)₂, NR⁴C(O)R⁴, NR⁴C(O)OR⁴, and NR⁴C(O)N(R⁴)₂.

In certain embodiments n is 4.

In certain embodiments each R^(X) and R^(Y) is independently chosen fromH and fluoro.

In certain embodiments one of R^(X) is independently fluoro.

In certain embodiments A¹, A², and A³ are N; A⁴ is CH; n is 4; Z¹ is C;Z² and Z³ are N; Z⁴ is S; and R³ is chosen from N(R⁴)₂, NR⁴C(O)R⁴,NR⁴C(O)OR⁴, and NR⁴C(O)N(R⁴)₂.

In certain embodiments A¹ is C; A² and A³ are N; A⁴ is S; n is 4; Z¹,Z², and Z³ are N; Z⁴ is CH; and R³ is chosen from C(O)N(R⁴)₂,S(O)N(R⁴)₂, S(O)₂N(R⁴)₂, C(O)R⁴, C(O)OR⁴.

In certain embodiments A¹, A², and A³ are N; A⁴ is CH; n is 4; Z¹, Z²,and Z³ are N; Z⁴ is CH; and R³ is chosen from N(R⁴)₂, NR⁴C(O)R⁴,NR⁴C(O)OR⁴, and NR⁴C(O)N(R⁴)₂.

In some embodiments, the compound, or a pharmaceutically acceptable saltthereof, has structural Formula III:

or a salt thereof, wherein: n is chosen from 3, 4, and 5; each R^(X) andR^(Y) is independently chosen from alkyl, cyano, H, and halo, or twoR^(X) groups together with the atoms to which they are attachedoptionally form a cycloalkyl ring; A¹ is chosen from C and N; A², A³,and A⁴, are independently chosen from N, O, S, and CH, wherein at leastone of A¹, A², A³, and A⁴ is chosen from N, O, and S; Z¹ is C; Z², Z³and Z⁴ are independently chosen from N and CH, wherein at least one ofZ¹, Z², Z³, and Z⁴ is N; R¹ and R² are each independently chosen fromalkenyl, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, halo,haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, andheterocycloalkylalkyl, wherein R¹ and R² each may be optionallysubstituted with one to three R^(Z) groups, wherein R¹ and R² togetherwith the atoms to which they are attached optionally form an heteroaryl,or heterocycloalkyl ring, which may be optionally substituted with oneto three R^(Z) groups; R³ is chosen from alkenyl, alkoxy, alkyl, aryl,arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,hydroxyl, C(R⁴)₂C(O)R⁴, C(R⁴)₂C(O)N(R⁴)₂, C(R⁴)₂N(R⁴)₂, C(R⁴)₂NR⁴C(O)R⁴,C(R⁴)₂NR⁴C(O)OR⁴, C(R⁴)₂NR⁴C(O)N(R⁴)₂, C(R⁴)₂NR⁴S(O)R⁴,C(R⁴)₂NR⁴S(O)₂R⁴, N(R⁴)₂, NR⁴C(O)R⁴, NR⁴C(O)OR⁴, NR⁴C(O)N(R⁴)₂,NR⁴S(O)R⁴, NR⁴S(O)₂R⁴, C(O)N(R⁴)₂, S(O)N(R⁴)₂, S(O)₂N(R⁴)₂, C(O)R⁴, SR⁴,S(O)R⁴, and S(O)₂R⁴; wherein each R³ may be optionally substituted withone to three R^(Z) groups; each R⁴ is independently chosen from alkenyl,alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H,halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,heterocycloalkylalkyl, and hydroxyl, wherein each R⁴ may be optionallysubstituted with one to three R^(Z) groups, wherein two R⁴ groupstogether with the atoms to which they are attached optionally form anheteroaryl, or heterocycloalkyl ring, which may be optionallysubstituted with one to three R^(Z) groups; each R^(Z) group isindependently chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl,alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl,alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl,alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl,alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl,alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl,aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano,cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylhaloalkyl,cycloalkyloxy, H, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl,haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl,haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl,haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl,haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl,haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl,haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl,haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl,halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy,haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl,haloheterocycloalkylalkyloxy, haloheterocycloalkyloxy, heteroaryl,heteroarylalkyl, heteroarylalkyloxy, heteroarylhaloalkyl, heteroaryloxy,heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy,heterocycloalkylhaloalkyl, heterocycloalkyloxy, hydroxyl, oxo, N(R⁵)₂,NR⁵C(O)R⁵, NR⁵C(O)OR⁵, NR⁵C(O)N(R⁵)₂, NR⁵S(O)R⁵, NR⁵S(O)₂R⁵, C(O)N(R⁵)₂,S(O)N(R⁵)₂, S(O)₂N(R⁵)₂, C(O)R⁵, C(O)OR⁵, SR⁵, S(O)R⁵, and S(O)₂R⁵; eachR⁵ is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl,cyano, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, whereintwo R⁵ groups together with the atoms to which they are attachedoptionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkylring, which may be optionally substituted with one to three R^(X)groups; and R⁶ is chosen from, alkyl, cyano, cycloalkyl, H, halo,haloalkyl, and heterocycloalkyl, wherein R³ and R⁶ groups together withthe atoms to which they are attached optionally form an aryl,cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may beoptionally substituted with one to three R^(Z) groups.

The In certain embodiments A¹ is C; A² and A³ are N; and A⁴ is S.

In certain embodiments A¹, A², and A³ are N; and A⁴ is CH.

In certain embodiments n is 4.

In certain embodiments each R^(X) and R^(Y) is independently chosen fromH and fluoro.

In certain embodiments one of R^(X) is independently fluoro.

In certain embodiments R¹ is methyl; and R² is H.

In certain embodiments R¹ is methyl; R² is H; and one of R^(X) isindependently fluoro.

In certain embodiments; Z² and Z³ are N; Z⁴ is CH; R³ is chosen fromN(R⁴)₂, NR⁴C(O)R⁴, NR⁴C(O)OR⁴, and NR⁴C(O)N(R⁴)₂; and R⁶ is H.

In certain embodiments A¹ is C; A² and A³ are N; A⁴ is S; n is 4; Z² andZ³ are N; Z⁴ is CH; R³ is chosen from N(R⁴)₂, NR⁴C(O)R⁴, NR⁴C(O)OR⁴, andNR⁴C(O)N(R⁴)₂; and R⁶ is H.

In certain embodiments A¹, A², and A³ are N; A⁴ is CH; n is 4; Z² and Z³are N; Z⁴ is CH; R³ is chosen from N(R⁴)₂, NR⁴C(O)R⁴, NR⁴C(O)OR⁴, andNR⁴C(O)N(R⁴)₂; and R⁶ is H.

In some embodiments, the compound, or a pharmaceutically acceptable saltthereof, has structural Formula IV:

or a salt thereof, wherein: R^(X) is chosen from fluoro and H; R¹ ischosen from alkenyl, alkyl, aryl, arylalkyl, cycloalkyl,cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, and heterocycloalkylalkyl, wherein R¹ may beoptionally substituted with one to three R^(Z) groups; each R⁴ isindependently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl,cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl,wherein R⁴ may be optionally substituted with one to three R^(Z) groups;each R^(Z) group is independently chosen from alkenyl, alkoxy,alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl,alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl,alkoxyheteroarylalkyl, alkoxyheterocycloalkyl,alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl,alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl,alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl,aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano,cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylhaloalkyl,cycloalkyloxy, H, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl,haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl,haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl,haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl,haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl,haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl,haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl,haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl,halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy,haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl,haloheterocycloalkylalkyloxy, haloheterocycloalkyloxy, heteroaryl,heteroarylalkyl, heteroarylalkyloxy, heteroarylhaloalkyl, heteroaryloxy,heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy,heterocycloalkylhaloalkyl, heterocycloalkyloxy, hydroxyl, oxo, N(R⁵)₂,NR⁵C(O)R⁵, NR⁵C(O)OR⁵, NR⁵C(O)N(R⁵)₂, NR⁵S(O)R⁵, NR⁵S(O)₂R⁵, C(O)N(R⁵)₂,S(O)N(R⁵)₂, S(O)₂N(R⁵)₂, C(O)R⁵, C(O)OR⁵, SR⁵, S(O)R⁵, and S(O)₂R⁵; andeach R⁵ is independently chosen from alkenyl, alkoxy, alkyl, aryl,arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, whereintwo R⁵ groups together with the atoms to which they are attachedoptionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkylring, which may be optionally substituted with one to three R^(X)groups.

In particular embodiments, R¹ is methyl.

In some embodiments, the compound, or a pharmaceutically acceptable saltthereof, has structural Formula V:

or a salt thereof, wherein: R^(X) is chosen from fluoro and H; R¹ ischosen from alkenyl, alkyl, aryl, arylalkyl, cycloalkyl,cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, and heterocycloalkylalkyl, wherein R¹ may beoptionally substituted with one to three R^(Z) groups; each R⁴ isindependently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl,cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl,wherein R⁴ may be optionally substituted with one to three R^(Z) groups;each R^(Z) group is independently chosen from alkenyl, alkoxy,alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl,alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl,alkoxyheteroarylalkyl, alkoxyheterocycloalkyl,alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl,alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl,alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl,aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano,cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylhaloalkyl,cycloalkyloxy, H, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl,haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl,haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl,haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl,haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl,haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl,haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl,haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl,halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy,haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl,haloheterocycloalkylalkyloxy, haloheterocycloalkyloxy, heteroaryl,heteroarylalkyl, heteroarylalkyloxy, heteroarylhaloalkyl, heteroaryloxy,heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy,heterocycloalkylhaloalkyl, heterocycloalkyloxy, hydroxyl, oxo, N(R⁵)₂,NR⁵C(O)R⁵, NR⁵C(O)OR⁵, NR⁵C(O)N(R⁵)₂, NR⁵S(O)R⁵, NR⁵S(O)₂R⁵, C(O)N(R⁵)₂,S(O)N(R⁵)₂, S(O)₂N(R⁵)₂, C(O)R⁵, C(O)OR⁵, SR⁵, S(O)R⁵, and S(O)₂R⁵; andeach R⁵ is independently chosen from alkenyl, alkoxy, alkyl, aryl,arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, whereintwo R⁵ groups together with the atoms to which they are attachedoptionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkylring, which may be optionally substituted with one to three R^(X)groups.

In some embodiments, the compound, or a pharmaceutically acceptable saltthereof, has structural Formula VI:

or a salt thereof, wherein: R^(X) is chosen from fluoro and H; R¹ ischosen from alkenyl, alkyl, aryl, arylalkyl, cycloalkyl,cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, and heterocycloalkylalkyl, wherein R¹ may beoptionally substituted with one to three R^(Z) groups; each R⁴ isindependently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl,cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl,wherein R⁴ may be optionally substituted with one to three R^(Z) groups;each R^(Z) group is independently chosen from alkenyl, alkoxy,alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl,alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl,alkoxyheteroarylalkyl, alkoxyheterocycloalkyl,alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl,alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl,alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl,aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano,cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylhaloalkyl,cycloalkyloxy, H, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl,haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl,haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl,haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl,haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl,haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl,haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl,haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl,halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy,haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl,haloheterocycloalkylalkyloxy, haloheterocycloalkyloxy, heteroaryl,heteroarylalkyl, heteroarylalkyloxy, heteroarylhaloalkyl, heteroaryloxy,heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy,heterocycloalkylhaloalkyl, heterocycloalkyloxy, hydroxyl, oxo, N(R⁵)₂,NR⁵C(O)R⁵, NR⁵C(O)OR⁵, NR⁵C(O)N(R⁵)₂, NR⁵S(O)R⁵, NR⁵S(O)₂R⁵, C(O)N(R⁵)₂,S(O)N(R⁵)₂, S(O)₂N(R⁵)₂, C(O)R⁵, C(O)OR⁵, SR⁵, S(O)R⁵, and S(O)₂R⁵; andeach R⁵ is independently chosen from alkenyl, alkoxy, alkyl, aryl,arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, whereintwo R⁵ groups together with the atoms to which they are attachedoptionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkylring, which may be optionally substituted with one to three R^(X)groups.

In some embodiments, the compound, or a pharmaceutically acceptable saltthereof, has structural Formula VII:

or a salt thereof, wherein: R^(X) is chosen from fluoro and H; each ofR^(Z1) and R^(Z2) is independently chosen from alkenyl, alkoxy,alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl,alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl,alkoxyheteroarylalkyl, alkoxyheterocycloalkyl,alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl,alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl,alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl,aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano,cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylhaloalkyl,cycloalkyloxy, H, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl,haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl,haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl,haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl,haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl,haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl,haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl,haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl,halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy,haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl,haloheterocycloalkylalkyloxy, haloheterocycloalkyloxy, heteroaryl,heteroarylalkyl, heteroarylalkyloxy, heteroarylhaloalkyl, heteroaryloxy,heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy,heterocycloalkylhaloalkyl, heterocycloalkyloxy, hydroxyl, and oxo.

In some embodiments, the compound, or a pharmaceutically acceptable saltthereof, is chosen from structural Formula VIIa or VIIb:

or a salt thereof, wherein: R^(X) is chosen from fluoro and H; each ofR^(Z1) and R^(Z2) is independently chosen from alkenyl, alkoxy,alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl,alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl,alkoxyheteroarylalkyl, alkoxyheterocycloalkyl,alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl,alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl,alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl,aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano,cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylhaloalkyl,cycloalkyloxy, H, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl,haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl,haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl,haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl,haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl,haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl,haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl,haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl,halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy,haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl,haloheterocycloalkylalkyloxy, haloheterocycloalkyloxy, heteroaryl,heteroarylalkyl, heteroarylalkyloxy, heteroarylhaloalkyl, heteroaryloxy,heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy,heterocycloalkylhaloalkyl, heterocycloalkyloxy, hydroxyl, and oxo.

In certain embodiments R^(X) is chosen from fluoro and H; and each ofR^(Z1) and R^(Z2) is independently chosen from alkyl, cycloalkyl,cycloalkylhaloalkyl, cycloalkyloxy, H, haloalkoxy, haloalkoxyaryl,haloalkyl, halocycloalkyloxy, heterocycloalkyl, and heterocycloalkyloxy.

In certain embodiments R^(X) is chosen from fluoro and H; each of R^(Z1)and R^(Z2) is independently chosen from H,

In some embodiments, the compound, or a pharmaceutically acceptable saltthereof, has structural Formula VIII:

or a salt thereof, wherein: R^(X) is chosen from fluoro and H; R^(Z1) ischosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl,alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl,alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl,alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl,alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl,alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl,aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano,cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylhaloalkyl,cycloalkyloxy, H, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl,haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl,haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl,haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl,haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl,haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl,haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl,haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl,halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy,haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl,haloheterocycloalkylalkyloxy, haloheterocycloalkyloxy, heteroaryl,heteroarylalkyl, heteroarylalkyloxy, heteroarylhaloalkyl, heteroaryloxy,heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy,heterocycloalkylhaloalkyl, heterocycloalkyloxy, hydroxyl, and oxo.

In particular embodiments the compound is chosen from Examples 1-609 andProphetic Examples 1-2 as disclosed herein.

Also provided are embodiments wherein any of embodiment above inparagraphs [0006] and [0106]-[0138] above may be combined with any oneor more of these embodiments, provided the combination is not mutuallyexclusive.

Pharmaceutical Compositions

While it may be possible for the compounds of the subject disclosure tobe administered as the raw chemical, it is also possible to present themas a pharmaceutical formulation. Accordingly, provided herein arepharmaceutical formulations which comprise one or more of certaincompounds disclosed herein, or one or more pharmaceutically acceptablesalts, esters, prodrugs, amides, or solvates thereof, together with oneor more pharmaceutically acceptable carriers thereof and optionally oneor more other therapeutic ingredients. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof. Properformulation is dependent upon the route of administration chosen. Any ofthe well-known techniques, carriers, and excipients may be used assuitable and as understood in the art; e.g., in Remington'sPharmaceutical Sciences. The pharmaceutical compositions disclosedherein may be manufactured in any manner known in the art, e.g., bymeans of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous, intraarticular,and intramedullary), intraperitoneal, transmucosal, transdermal, rectaland topical (including dermal, buccal, sublingual and intraocular)administration although the most suitable route may depend upon forexample the condition and disorder of the recipient. The formulationsmay conveniently be presented in unit dosage form and may be prepared byany of the methods well known in the art of pharmacy. Typically, thesemethods include the step of bringing into association a compound of thesubject disclosure or a pharmaceutically acceptable salt, ester, amide,prodrug or solvate thereof (“active ingredient”) with the carrier whichconstitutes one or more accessory ingredients. In general, theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation.

Compounds described herein can be administered as follows:

Oral Administration

The compounds of the present invention may be administered orally,including swallowing, so the compound enters the gastrointestinal tract,or is absorbed into the blood stream directly from the mouth, includingsublingual or buccal administration.

Suitable compositions for oral administration include solid formulationssuch as tablets, pills, cachets, lozenges and hard or soft capsules,which can contain liquids, gels, powders, or granules.

In a tablet or capsule dosage form the amount of drug present may befrom about 0.05% to about 95% by weight, more typically from about 2% toabout 50% by weight of the dosage form.

In addition, tablets or capsules may contain a disintegrant, comprisingfrom about 0.5% to about 35% by weight, more typically from about 2% toabout 25% of the dosage form. Examples of disintegrants include methylcellulose, sodium or calcium carboxymethyl cellulose, croscarmellosesodium, polyvinylpyrrolidone, hydroxypropyl cellulose, starch and thelike.

Suitable binders, for use in a tablet, include gelatin, polyethyleneglycol, sugars, gums, starch, hydroxypropyl cellulose and the like.Suitable diluents, for use in a tablet, include mannitol, xylitol,lactose, dextrose, sucrose, sorbitol and starch.

Suitable surface active agents and glidants, for use in a tablet orcapsule, may be present in amounts from about 0.1% to about 3% byweight, and include polysorbate 80, sodium dodecyl sulfate, talc andsilicon dioxide.

Suitable lubricants, for use in a tablet or capsule, may be present inamounts from about 0.1% to about 5% by weight, and include calcium, zincor magnesium stearate, sodium stearyl fumarate and the like.

Tablets may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed withbinders, inert diluents, or lubricating, surface active or dispersingagents. Molded tablets may be made by molding in a suitable machine amixture of the powdered compound moistened with a liquid diluent. Dyesor pigments may be added to tablets for identification or tocharacterize different combinations of active compound doses.

Liquid formulations can include emulsions, solutions, syrups, elixirsand suspensions, which can be used in soft or hard capsules. Suchformulations may include a pharmaceutically acceptable carrier, forexample, water, ethanol, polyethylene glycol, cellulose, or an oil. Theformulation may also include one or more emulsifying agents and/orsuspending agents.

Compositions for oral administration may be formulated as immediate ormodified release, including delayed or sustained release, optionallywith enteric coating.

In another embodiment, a pharmaceutical composition comprises atherapeutically effective amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

Parenteral Administration

Compounds of the present invention may be administered directly into theblood stream, muscle, or internal organs by injection, e.g., by bolusinjection or continuous infusion. Suitable means for parenteraladministration include intravenous, intra-muscular, subcutaneousintraarterial, intraperitoneal, intrathecal, intracranial, and the like.Suitable devices for parenteral administration include injectors(including needle and needle-free injectors) and infusion methods. Theformulations may be presented in unit-dose or multi-dose containers, forexample sealed ampoules and vials.

Most parenteral formulations are aqueous solutions containingexcipients, including salts, buffering, suspending, stabilizing and/ordispersing agents, antioxidants, bacteriostats, preservatives, andsolutes which render the formulation isotonic with the blood of theintended recipient, and carbohydrates.

Parenteral formulations may also be prepared in a dehydrated form (e.g.,by lyophilization) or as sterile non-aqueous solutions. Theseformulations can be used with a suitable vehicle, such as sterile water.Solubility-enhancing agents may also be used in preparation ofparenteral solutions.

Compositions for parenteral administration may be formulated asimmediate or modified release, including delayed or sustained release.Compounds may also be formulated as depot preparations. Such long actingformulations may be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, the compounds may be formulated with suitable polymeric orhydrophobic materials (for example as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

Topical Administration

Compounds of the present invention may be administered topically (forexample to the skin, mucous membranes, ear, nose, or eye) ortransdermally. Formulations for topical administration can include, butare not limited to, lotions, solutions, creams, gels, hydrogels,ointments, foams, implants, patches and the like. Carriers that arepharmaceutically acceptable for topical administration formulations caninclude water, alcohol, mineral oil, glycerin, polyethylene glycol andthe like. Topical administration can also be performed by, for example,electroporation, iontophoresis, phonophoresis and the like.

Typically, the active ingredient for topical administration may comprisefrom 0.001% to 10% w/w (by weight) of the formulation. In certainembodiments, the active ingredient may comprise as much as 10% w/w; lessthan 5% w/w; from 2% w/w to 5% w/w; or from 0.1% to 1% w/w of theformulation.

Compositions for topical administration may be formulated as immediateor modified release, including delayed or sustained release.

Rectal, Buccal, and Sublingual Administration

Suppositories for rectal administration of the compounds of the presentinvention can be prepared by mixing the active agent with a suitablenon-irritating excipient such as cocoa butter, synthetic mono-, di-, ortriglycerides, fatty acids, or polyethylene glycols which are solid atordinary temperatures but liquid at the rectal temperature, and whichwill therefore melt in the rectum and release the drug.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

Administration by Inhalation

For administration by inhalation, compounds may be convenientlydelivered from an insufflator, nebulizer pressurized packs or otherconvenient means of delivering an aerosol spray or powder. Pressurizedpacks may comprise a suitable propellant such asdichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. Alternatively, foradministration by inhalation or insufflation, the compounds according tothe disclosure may take the form of a dry powder composition, forexample a powder mix of the compound and a suitable powder base such aslactose or starch. The powder composition may be presented in unitdosage form, in for example, capsules, cartridges, gelatin or blisterpacks from which the powder may be administered with the aid of aninhalator or insufflator.

Other carrier materials and modes of administration known in thepharmaceutical art may also be used. Pharmaceutical compositions of theinvention may be prepared by any of the well-known techniques ofpharmacy, such as effective formulation and administration procedures.Preferred unit dosage formulations are those containing an effectivedose, as herein recited, or an appropriate fraction thereof, of theactive ingredient. The precise amount of compound administered to apatient will be the responsibility of the attendant physician. Thespecific dose level for any particular patient will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, general health, sex, diets, time ofadministration, route of administration, rate of excretion, drugcombination, the precise disorder being treated, and the severity of theindication or condition being treated. In addition, the route ofadministration may vary depending on the condition and its severity. Theabove considerations concerning effective formulations andadministration procedures are well known in the art and are described instandard textbooks. Formulation of drugs is discussed in, for example,Hoover, John E., Remington's Pharmaceutical Sciences, Mack PublishingCo., Easton, Pa., 1975; Liberman, et al., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Kibbe, et al., Eds.,Handbook of Pharmaceutical Excipients (3^(rd) Ed.), AmericanPharmaceutical Association, Washington, 1999.

Methods of Treatment

The present disclosure provides compounds and pharmaceuticalcompositions that inhibit glutaminase activity, particularly GLS1activity and are thus useful in the treatment or prevention of disordersassociated with GLS1. Compounds and pharmaceutical compositions of thepresent disclosure selectively modulate GLS1 and are thus useful in thetreatment or prevention of a range of disorders associated with GLS1 andinclude, but are not limited to, cancer, immunological or neurologicaldiseases associated with GLS1.

Neurological Disorders

In some embodiments, the compounds and pharmaceutical compositions ofthe present disclosure may be useful in the treatment or prevention ofneurological diseases.

The most common neurotransmitter is glutamate, derived from theenzymatic conversion of glutamine via glutaminase. High levels ofglutamate have been shown to be neurotoxic. Following traumatic insultto neuronal cells, there occurs a rise in neurotransmitter release,particularly glutamate. Accordingly, inhibition of glutaminase has beenhypothesized as a means of treatment following an ischemic insult, suchas stroke.

Huntington's disease is a progressive, fatal neurological condition. Ingenetic mouse models of Huntington's disease, it was observed that theearly manifestation of the disease correlated with dysregulatedglutamate release (Raymond et al., Neuroscience, 2011). InHIV-associated dementia, HIV infected macrophages exhibit upregulatedglutaminase activity and increased glutamate release, leading toneuronal damage (Huang et al., J. Neurosci., 2011). Similarly, inanother neurological disease, the activated microglia in Rett Syndromerelease glutamate causing neuronal damage. The release of excessglutamate has been associated with the up-regulation of glutaminase(Maezawa et al., J. Neurosci, 2010). In mice bred to have reducedglutaminase levels, sensitivity to psychotic-stimulating drugs, such asamphetamines, was dramatically reduced, thus suggesting that glutaminaseinhibition may be beneficial in the treatment of schizophrenia(Gaisler-Salomon et al., Neuropsychopharmacology, 2009). Bipolardisorder is a devastating illness that is marked by recurrent episodesof mania and depression. This disease is treated with mood stabilizerssuch as lithium and valproate; however, chronic use of these drugsappear to increase the abundance of glutamate receptors (Nanavati etal., J. Neurochem., 2011), which may lead to a decrease in the drug'seffectiveness over time. Thus, an alternative treatment may be to reducethe amount of glutamate by inhibiting glutaminase. This may or may notbe in conjunction with the mood stabilizers. Memantine, a partialantagonist of N-methyl-D-aspartate receptor (NMDAR), is an approvedtherapeutic in the treatment of Alzheimer's disease. Currently, researchis being conducted looking at memantine as a means of treating vasculardementia and Parkinson's disease (Oliverares et al., Curr. AlzheimerRes., 2011). Since memantine has been shown to partially block the NMDAglutamate receptor also, it is not unresasonable to speculate thatdecreasing glutamate levels by inhibiting glutaminase could also treatAlzheimer's disease, vascular dementia and Parkinson's disease.Alzheimer's disease, bipolar disorder, HIV-associated dementia,Huntington's disease, ischemic insult, Parkinson's disease,schizophrenia, stroke, traumatic insult and vascular dementia are but afew of the neurological diseases that have been correlated to increasedlevels of glutamate. Thus, inhibiting glutaminase with a compounddescribed herein can reduce or prevent neurological diseases. Therefore,in certain embodiments, the compounds may be used for the treatment orprevention of neurological diseases.

Immunological Disorders

In some embodiments, the compounds and pharmaceutical compositions ofthe present disclosure may be useful in the treatment or prevention ofimmunological diseases.

Activation of T lymphocytes induces cell growth, proliferation, andcytokine production, thereby placing energetic and biosynthetic demandson the cell. Glutamine serves as an amine group donor for nucleotidesynthesis, and glutamate, the first component in glutamine metabolism,plays a direct role in amino acid and glutathione synthesis, as well asbeing able to enter the Krebs cycle for energy production (Carr et al.,J. Immunol., 2010). Mitogen-induced T cell proliferation and cytokineproduction require high levels of glutamine metabolism, thus inhibitingglutaminase may serve as a means of immune modulation. In multiplesclerosis, an inflammatory autoimmune disease, the activated microgliaexhibit up-regulated glutaminase and release increased levels ofextracellular glutamate. Glutamine levels are lowered by sepsis, injury,burns, surgery and endurance exercise (Calder et al., Amino Acids,1999). These situations put the individual at risk of immunosuppression.In fact, in general, glutaminase gene expression and enzyme activity areboth increased during T cell activity. Patients given glutaminefollowing bone marrow transplantation resulted in a lower level ofinfection and reduced graft v. host disease (Crowther, Proc. Nutr. Soc.,2009). T cell proliferation and activiation is involved in manyimmunological diseases, such as inflammatory bowel disease, Crohn'sdisease, sepsis, psoriasis, arthritis (including rheumatoid arthritis),multiple sclerosis, graft v. host disease, infections, lupus anddiabetes. In an embodiment of the invention, the compounds describedherein can be used to treat or prevent immunological diseases.

Cancer

In some embodiments, the compounds and pharmaceutical compositions ofthe present disclosure may be useful in the treatment or prevention ofcancer.

In addition to serving as the basic building blocks of proteinsynthesis, amino acids have been shown to contribute to many processescritical for growing and dividing cells, and this is particularly truefor cancer cells. Nearly all definitions of cancer include reference todysregulated proliferation. Numerous studies on glutamine metabolism incancer indicate that many tumors are avid glutamine consumers (Souba,Ann. Surg., 1993; Collins et al., J. Cell. Physiol., 1998; Medina, J.Nutr., 2001; Shanware et al., J. Mol. Med., 2011). An embodiment of theinvention is the use of the compounds described herein for the treatmentof cancer.

In some embodiments, the compounds of the present disclosure may be usedto prevent or treat cancer, wherein the cancer is one or a variant ofAcute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML),Adrenocortical Carcinoma, AIDS-Related Cancers (Kaposi Sarcoma andLymphoma), Anal Cancer, Appendix Cancer, Atypical Teratoid/RhabdoidTumor, Basal Cell Carcinoma, Bile Duct Cancer (including Extrahepatic),Bladder Cancer, Bone Cancer (including Osteosarcoma and MalignantFibrous Histiocytoma), Brain Tumor (such as Astrocytomas, Brain andSpinal Cord Tumors, Brain Stem Glioma, Central Nervous System AtypicalTeratoid/Rhabdoid Tumor, Central Nervous System Embryonal Tumors,Craniopharyngioma, Ependymoblastoma, Ependymoma, Medulloblastoma,Medulloepithelioma, Pineal Parenchymal Tumors of IntermediateDifferentiation, Supratentorial Primitive Neuroectodermal Tumors andPineoblastoma), Breast Cancer, Bronchial Tumors, Burkitt Lymphoma, BasalCell Carcinoma, Bile Duct Cancer (including Extrahepatic), BladderCancer, Bone Cancer (including Osteosarcoma and Malignant FibrousHistiocytoma), Carcinoid Tumor, Carcinoma of Unknown Primary, CentralNervous System (such as Atypical Teratoid/Rhabdoid Tumor, EmbryonalTumors and Lymphoma), Cervical Cancer, Childhood Cancers, Chordoma,Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML),Chronic Myeloproliferative Disorders, Colon Cancer, Colorectal Cancer,Craniopharyngioma, Cutaneous T-Cell Lymphoma (Mycosis Fungoides andSézary Syndrome), Duct, Bile (Extrahepatic), Ductal Carcinoma In Situ(DCIS), Embryonal Tumors (Central Nervous System), Endometrial Cancer,Ependymoblastoma, Ependymoma, Esophageal Cancer, Esthesioneuroblastoma,Ewing Sarcoma Family of Tumors, Extracranial Germ Cell Tumor,Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer(like Intraocular Melanoma, Retinoblastoma), Fibrous Histiocytoma ofBone (including Malignant and Osteosarcoma) Gallbladder Cancer, Gastric(Stomach) Cancer, Gastrointestinal Carcinoid Tumor, GastrointestinalStromal Tumors (GIST), Germ Cell Tumor (Extracranial, Extragonadal,Ovarian), Gestational Trophoblastic Tumor, Glioma, Hairy Cell Leukemia,Head and Neck Cancer, Heart Cancer, Hepatocellular (Liver) Cancer,Histiocytosis, Langerhans Cell, Hodgkin Lymphoma, Hypopharyngeal Cancer,Intraocular Melanoma, Islet Cell Tumors (Endocrine, Pancreas), KaposiSarcoma, Kidney (including Renal Cell), Langerhans Cell Histiocytosis,Laryngeal Cancer, Leukemia (including Acute Lymphoblastic (ALL), AcuteMyeloid (AML), Chronic Lymphocytic (CLL), Chronic Myelogenous (CML),Hairy Cell), Lip and Oral Cavity Cancer, Liver Cancer (Primary), LobularCarcinoma In Situ (LCIS), Lung Cancer (Non-Small Cell and Small Cell),Lymphoma (AIDS-Related, Burkitt, Cutaneous T-Cell (Mycosis Fungoides andSézary Syndrome), Hodgkin, Non-Hodgkin, Primary Central Nervous System(CNS), Macroglobulinemia, Waldenström, Male Breast Cancer, MalignantFibrous Histiocytoma of Bone and Osteosarcoma, Medulloblastoma,Medulloepithelioma, Melanoma (including Intraocular (Eye)), Merkel CellCarcinoma, Mesothelioma (Malignant), Metastatic Squamous Neck Cancerwith Occult Primary, Midline Tract Carcinoma Involving NUT Gene, MouthCancer, Multiple Endocrine Neoplasia Syndromes, Multiple Myeloma/PlasmaCell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndromes,Myelodysplastic/Myeloproliferative Neoplasms, Myelogenous Leukemia,Chronic (CML), Myeloid Leukemia, Acute (AML), Myeloma and MultipleMyeloma, Myeloproliferative Disorders (Chronic), Nasal Cavity andParanasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma,Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, OralCavity Cancer, Lip and, Oropharyngeal Cancer, Osteosarcoma and MalignantFibrous Histiocytoma of Bone, Ovarian Cancer (such as Epithelial, GermCell Tumor, and Low Malignant Potential Tumor), Pancreatic Cancer(including Islet Cell Tumors), Papillomatosis, Paraganglioma, ParanasalSinus and Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer,Pharyngeal Cancer, Pheochromocytoma, Pineal Parenchymal Tumors ofIntermediate Differentiation, Pineoblastoma and Supratentorial PrimitiveNeuroectodermal Tumors, Pituitary Tumor, Plasma Cell Neoplasm/MultipleMyeloma, Pleuropulmonary Blastoma, Pregnancy and Breast Cancer, PrimaryCentral Nervous System (CNS) Lymphoma, Prostate Cancer, Rectal Cancer,Renal Cell (Kidney) Cancer, Renal Pelvis and Ureter, Transitional CellCancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoma(like Ewing Sarcoma Family of Tumors, Kaposi, Soft Tissue, Uterine),Sézary Syndrome, Skin Cancer (such as Melanoma, Merkel Cell Carcinoma,Nonmelanoma), Small Cell Lung Cancer, Small Intestine Cancer, SoftTissue Sarcoma, Squamous Cell Carcinoma, Squamous Neck Cancer withOccult Primary, Metastatic, Stomach (Gastric) Cancer, SupratentorialPrimitive Neuroectodermal Tumors, T-Cell Lymphoma (Cutaneous, MycosisFungoides and Sézary Syndrome), Testicular Cancer, Throat Cancer,Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancerof the Renal Pelvis and Ureter, Trophoblastic Tumor (Gestational),Unknown Primary, Unusual Cancers of Childhood, Ureter and Renal Pelvis,Transitional Cell Cancer, Urethral Cancer, Uterine Cancer, Endometrial,Uterine Sarcoma, Waldenström Macroglobulinemia or Wilms Tumor.

In certain embodiments, the cancer to be treated is one specific toT-cells such as T-cell lymphomia and lymphblastic T-cell leukemia.

In some embodiments, methods described herein are used to treat adisease condition comprising administering to a subject in need thereofa therapeutically effective amount of a compound of Formula I orpharmaceutically acceptable salt thereof, wherein the condition iscancer which has developed resistance to chemotherapeutic drugs and/orionizing radiation.

Combinations and Combination Therapy

The compounds of the present invention can be used, alone or incombination with other pharmaceutically active compounds, to treatconditions such as those previously described hereinabove. Thecompound(s) of the present invention and other pharmaceutically activecompound(s) can be administered simultaneously (either in the samedosage form or in separate dosage forms) or sequentially. Accordingly,in one embodiment, the present invention comprises methods for treatinga condition by administering to the subject a therapeutically-effectiveamount of one or more compounds of the present invention and one or moreadditional pharmaceutically active compounds.

In another embodiment, there is provided a pharmaceutical compositioncomprising one or more compounds of the present invention, one or moreadditional pharmaceutically active compounds, and a pharmaceuticallyacceptable carrier.

In another embodiment, the one or more additional pharmaceuticallyactive compounds is selected from the group consisting of anti-cancerdrugs, anti-proliferative drugs, and anti-inflammatory drugs.

GLS1 inhibitor compositions described herein are also optionally used incombination with other therapeutic reagents that are selected for theirtherapeutic value for the condition to be treated. In general, thecompounds described herein and, in embodiments where combination therapyis employed, other agents do not have to be administered in the samepharmaceutical composition and, because of different physical andchemical characteristics, are optionally administered by differentroutes. The initial administration is generally made according toestablished protocols and then, based upon the observed effects, thedosage, modes of administration and times of administration subsequentlymodified. In certain instances, it is appropriate to administer a GLS1inhibitor compound, as described herein, in combination with anothertherapeutic agent. By way of example only, the therapeutic effectivenessof a GLS1 inhibitor is enhanced by administration of another therapeuticagent (which also includes a therapeutic regimen) that also hastherapeutic benefit. Regardless of the disease, disorder or conditionbeing treated, the overall benefit experienced by the patient is eithersimply additive of the two therapeutic agents or the patient experiencesan enhanced (i.e., synergistic) benefit. Alternatively, if a compounddisclosed herein has a side effect, it may be appropriate to administeran agent to reduce the side effect; or the therapeutic effectiveness ofa compound described herein may be enhanced by administration of anadjuvant.

Therapeutically effective dosages vary when the drugs are used intreatment combinations. Methods for experimentally determiningtherapeutically effective dosages of drugs and other agents for use incombination treatment regimens are documented methodologies. Combinationtreatment further includes periodic treatments that start and stop atvarious times to assist with the clinical management of the patient. Inany case, the multiple therapeutic agents (one of which is a GLS1inhibitor as described herein) may be administered in any order, orsimultaneously. If simultaneously, the multiple therapeutic agents areoptionally provided in a single, unified form, or in multiple forms (byway of example only, either as a single pill or as two separate pills).

In some embodiments, one of the therapeutic agents is given in multipledoses, or both are given as multiple doses. If not simultaneous, thetiming between the multiple doses optionally varies from more than zeroweeks to less than twelve weeks.

In addition, the combination methods, compositions and formulations arenot to be limited to the use of only two agents, the use of multipletherapeutic combinations are also envisioned. It is understood that thedosage regimen to treat, prevent, or ameliorate the condition(s) forwhich relief is sought, is optionally modified in accordance with avariety of factors. These factors include the disorder from which thesubject suffers, as well as the age, weight, sex, diet, and medicalcondition of the subject. Thus, the dosage regimen actually employedvaries widely, in some embodiments, and therefore deviates from thedosage regimens set forth herein.

The pharmaceutical agents which make up the combination therapydisclosed herein are optionally a combined dosage form or in separatedosage forms intended for substantially simultaneous administration. Thepharmaceutical agents that make up the combination therapy areoptionally also administered sequentially, with either agent beingadministered by a regimen calling for two-step administration. Thetwo-step administration regimen optionally calls for sequentialadministration of the active agents or spaced-apart administration ofthe separate active agents. The time between the multiple administrationsteps ranges from a few minutes to several hours, depending upon theproperties of each pharmaceutical agent, such as potency, solubility,bioavailability, plasma half-life and kinetic profile of thepharmaceutical agent.

In another embodiment, a GLS1 inhibitor is optionally used incombination with procedures that provide additional benefit to thepatient. A GLS1 inhibitor and any additional therapies are optionallyadministered before, during or after the occurrence of a disease orcondition, and the timing of administering the composition containing aGLS1 inhibitor varies in some embodiments. Thus, for example, a GLS1inhibitor is used as a prophylactic and is administered continuously tosubjects with a propensity to develop conditions or diseases in order toprevent the occurrence of the disease or condition. A GLS1 inhibitor andcompositions are optionally administered to a subject during or as soonas possible after the onset of the symptoms. While embodiments of thepresent invention have been shown and described herein, it will beobvious to those skilled in the art that such embodiments are providedby way of example only. Numerous variations, changes, and substitutionswill now occur to those skilled in the art without departing from theinvention. It should be understood that in some embodiments of theinvention various alternatives to the embodiments described herein areemployed in practicing the invention.

A GLS1 inhibitor can be used in combination with anti-cancer drugs,including but not limited to the following classes: alkylating agents,anti-metabolites, plant alkaloids and terpenoids, topoisomeraseinhibitors, cytotoxic antibiotics, angiogenesis inhibitors and tyrosinekinase inhibitors.

For use in cancer and neoplastic diseases a GLS1 inhibitor may beoptimally used together with one or more of the following non-limitingexamples of anti-cancer agents: (1) alkylating agents, including but notlimited to cisplatin (PLATIN), carboplatin (PARAPLATIN), oxaliplatin(ELOXATIN), streptozocin (ZANOSAR), busulfan (MYLERAN) andcyclophosphamide (ENDOXAN); (2) anti-metabolites, including but notlimited to mercaptopurine (PURINETHOL), thioguanine, pentostatin(NIPENT), cytosine arabinoside (ARA-C), gemcitabine (GEMZAR),fluorouracil (CARAC), leucovorin (FUSILEV) and methotrexate(RHEUMATREX); (3) plant alkaloids and terpenoids, including but notlimited to vincristine (ONCOVIN), vinblastine and paclitaxel (TAXOL);(4) topoisomerase inhibitors, including but not limited to irinotecan(CAMPTOSAR), topotecan (HYCAMTIN) and etoposide (EPOSIN); (5) cytotoxicantibiotics, including but not limited to actinomycin D (COSMEGEN),doxorubicin (ADRIAMYCIN), bleomycin (BLENOXANE) and mitomycin (MITOSOL);(6) angiogenesis inhibitors, including but not limited to sunitinib(SUTENT) and bevacizumab (AVASTIN); and (7) tyrosine kinase inhibitors,including but not limited to imatinib (GLEEVEC), erlotinib (TARCEVA),lapatininb (TYKERB) and axitinib (INLYTA).

Where a subject is suffering from or at risk of suffering from aninflammatory condition, a GLS1 inhibitor compound described herein isoptionally used together with one or more agents or methods for treatingan inflammatory condition in any combination. Therapeuticagents/treatments for treating an autoimmune and/or inflammatorycondition include, but are not limited to any of the following examples:(1) corticosteroids, including but not limited to cortisone,dexamethasone, and methylprednisolone; (2) nonsteroidalanti-inflammatory drugs (NSAIDs), including but not limited toibuprofen, naproxen, acetaminophen, aspirin, fenoprofen (NALFON),flurbiprofen (ANSAID), ketoprofen, oxaprozin (DAYPRO), diclofenac sodium(VOLTAREN), diclofenac potassium (CATAFLAM), etodolac (LODINE),indomethacin (INDOCIN), ketorolac (TORADOL), sulindac (CLINORIL),tolmetin (TOLECTIN), meclofenamate (MECLOMEN), mefenamic acid (PONSTEL),nabumetone (RELAFEN) and piroxicam (FELDENE); (3) immunosuppressants,including but not limited to methotrexate (RHEUMATREX), leflunomide(ARAVA), azathioprine (IMURAN), cyclosporine (NEORAL, SANDIMMUNE),tacrolimus and cyclophosphamide (CYTOXAN); (4) CD20 blockers, includingbut not limited to rituximab (RITUXAN); (5) Tumor Necrosis Factor (TNF)blockers, including but not limited to etanercept (ENBREL), infliximab(REMICADE) and adalimumab (HUMIRA); (6) interleukin-1 receptorantagonists, including but not limited to anakinra (KINERET); (7)interleukin-6 inhibitors, including but not limited to tocilizumab(ACTEMRA); (8) interleukin-17 inhibitors, including but not limited toAIN457; (9) Janus kinase inhibitors, including but not limited totasocitinib; and (10) syk inhibitors, including but not limited tofostamatinib.

Compound Synthesis

Compounds of the present invention can be prepared using methodsillustrated in general synthetic schemes and experimental proceduresdetailed below. General synthetic schemes and experimental proceduresare presented for purposes of illustration and are not intended to belimiting. Starting materials used to prepare compounds of the presentinvention are commercially available or can be prepared using routinemethods known in the art.

List of Abbreviations

Ac₂O=acetic anhydride; AcCl=acetyl chloride; AcOH=acetic acid;AIBN=azobisisobutyronitrile; aq.=aqueous;BAST=bis(2-methoxyethyl)aminosulfur trifluoride; Bu₃SnH=tributyltinhydride; CD₃OD=deuterated methanol; CDCl₃=deuterated chloroform;CDI=1,1′-Carbonyldiimidazole; DAST=(diethylamino)sulfur trifluoride;DBU=1,8-diazabicyclo[5.4.0]undec-7-ene; DCM=dichloromethane;DEAD=diethyl azodicarboxylate; DIBAL-H=di-iso-butyl aluminium hydride;DIEA=DIPEA=N,N-diisopropylethylamine; DMAP=4-dimethylaminopyridine;DMF=N,N-dimethylformamide; DMSO-d₆=deuterated dimethyl sulfoxide;DMSO=dimethyl sulfoxide; DPPA=diphenylphosphoryl azide;EDC.HCl=EDCI.HCl=1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride; Et₂O=diethyl ether; EtOAc=ethyl acetate; EtOH=ethanol;h=hour; HATU=2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate methanaminium; HMDS=hexamethyldisilazane;HOBT=1-hydroxybenzotriazole; i-PrOH=isopropanol; LAH=lithiumaluminiumhydride; LDA=lithium diisopropyl amide; LiHMDS=Lithiumbis(trimethylsilyl)amide; MeCN=acetonitrile; MeOH=methanol; MP-carbonateresin=macroporous triethylammonium methylpolystyrene carbonate resin;MsCl=mesyl chloride; MTBE=methyl tertiary butyl ether;n-BuLi=n-butyllithium; NaHMDS=Sodium bis(trimethylsilyl)amide;NaOMe=sodium methoxide; NaOtBu=sodium t-butoxide;NBS=N-bromosuccinimide; NCS=N-chlorosuccinimide;NMP=N-Methyl-2-pyrrolidone;Pd(Ph₃)₄=tetrakis(triphenylphosphine)palladium(0);Pd₂(dba)₃=tris(dibenzylideneacetone)dipalladium(0);PdCl₂(PPh₃)₂=bis(triphenylphosphine)palladium(II) dichloride;PG=protecting group; prep-HPLC=preparative high-performance liquidchromatography; PMBCl=para-methoxybenzyl chloride;PyBop=(benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate; Pyr=pyridine; RT=room temperature;RuPhos=2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl;sat.=saturated; ss=saturated solution; t-BuOH=tert-butanol;T3P=Propylphosphonic Anhydride; TEA=Et₃N=triethylamine;TFA=trifluoroacetic acid; TFAA=trifluoroacetic anhydride;THF=tetrahydrofuran; Tot=toluene; TsCl=tosyl chloride;Xantphos=4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene;X-Phos=2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.

General Methods for Preparing Compounds

The following schemes can be used to practice the present invention.Additional structural groups, including but not limited to those definedelsewhere in the specification and not shown in the compounds describedin the schemes can be incorporated to give various compounds disclosedherein, or intermediate compounds which can, after further manipulationsusing techniques known to those skilled in the art, be converted tocompounds of the present invention. For example in certain embodimentsthe A-ring in the structures described in the schemes—wherein A is aheteroaromatic ring—can be substituted with various groups as definedherein.

One route for preparation of compounds of the present invention isdescribed in Scheme 1. A substituted functionalized halo-heteroaromaticamine is reacted with a suitable acyl chloride in the presence of a basesuch as DIEA or TEA in a solvent such as DMF, DCM or NMP. The resultingcarboxamide can be further functionalized, for example by Sonogashiracross-coupling reaction with a suitably functionalized hydroxy alkyne(Tetrahedron Lett. 16: 4467-4470). Typically the above transformation isperformed in the presence of a suitable Pd catalyst such as PdCl₂(PPh₃)₂or Pd(PPh₃)₄, a copper co-catalyst, typically a halide salt of copper(I), such as CuI or CuBr, and a base such as DIEA or TEA. Thetransformation can typically be run at RT or with mild heating in avariety of solvents, including DMF, toluene and EtOAc. Furtherfunctional group manipulations include hydrogenation of the resultingheteroaromatic alkyne derivative in the presence of a suitable Pdcatalyst (such as Pd/C or Pd(OH₂)) in a solvent such as EtOH, andconversion of the hydroxyl moiety into an azide, for example bytreatement with DPPA and a base such as TEA heating in a solvent such astoluene, according to the procedure published in Bose et al.,Tetrahedron Lett. 1977, 18, 1977-1980. Alternatively, the hydroxyl groupcould be converted into the corresponding mesylate or tosylate and thendisplaced with NaN₃ in a suitable polar solvent such as DMF. Theobtained azide derivative can then be progressed to the correspondingtriazole-4-carboxylic ester by copper-mediated azide-alkynecycloaddition with a suitable alkyl propriolate in the presence of abase (e.g. TEA or DIEA), and a copper (I) salt such as CuI, or a copper(II) salt such as CuSO₄ in the presence of a reducing agent such assodium ascorbate, in a solvent such as THF, DMSO, tBuOH or H₂O (H. C.Kolb, M. G. Finn and K. B. Sharpless, Angewandte Chemie InternationalEdition, 2001, 40 (11): 2004-2021). Finally, the desired amide in the4-position of the triazole ring can be installed by direct displacementof the carboxylic ester with a suitable amine heating in a polar solventsuch as DMF or MeOH. Alternatively, the same transformation could beachieved with a two-step sequence involving the base-mediated hydrolysisof the carboxylic ester followed by coupling of the resulting carboxylicacid with amine, using standard coupling reagents such as HATU, PyBOP orEDCI.HCl, in the presence of a suitable base such as TEA or DIEA, in apolar solvent such as DMF.

Another route for the preparation of compounds of the present inventionis described in Scheme 2. A suitably functionalized alkyne hydrazidecould be converted in the corresponding 1,3,4-thiadiazole 2-carboxylatederivative by acylation with ethyl chlorooxoacetate followed by heatingin a solvent such as toluene in the presence of P₂S₅. The resultingalkyne thiadiazole could be further functionalized by Sonogashiracross-coupling with a suitably substituted heteroaryl chloride, insimilar conditions to those described in Scheme 1 for suchtransformation. The resulting heteroaromatic alkyne can then be reducedby hydrogenation in the presence of a suitable Pd catalyst (such as Pd/Cor Pd(OH₂)) in a solvent such as EtOH. Finally, functional groupmanipulations similar to those described for Scheme 1 could be employedto progress the 2-carboxy ester thiadazoles into the desired2-carboxylic amides derivatives.

A further route of preparation of the compounds described in thisinvention is depicted in Scheme 3. A suitably functionalized alkylnitrile bearing a protected hydroxyl moiety can be converted to a5-alkyl-2-amino thiadazole by heating in the presence of TFA andhydrazinecarbothioamide. Suitable protecting groups for the hydroxylmoiety can be chosen amongst substituted ethers (e.g. benzyl ether,3,4-dimethoxy-benzylether, t-butyl ether, t-butyldimethylsilyl ether),esters or other suitable functional groups known to those skilled in theart (see also: P. G. M. Wutz, T. W. Greene, “Greene's protective Groupsin Organic Synthesis”, Fourth Edition, John Wiley & Sons). The obtainedthiadazole can then be progressed to the corresponding 2-carboxamidederivative by acylation with a suitable acyl chloride in the presence ofa base such as TEA or DIEA in a solvent such as DCM. Removal of thehydroxyl protecting group with techniques known to those skilled in theart (for example: reductive removal of a benzyl ether group; see also P.G. M. Wutz, T. W. Greene in reference cited above) can then enable theconversion of the liberated hydroxyl moiety into an azide group, withconditions similar to those described in Scheme 1, i.e. treatment withDPPA heating in the presence of a base such as TEA, or conversion to thecorresponding mesylate or tosylate followed by displacement with NaN₃ ina polar solvent like DMF. The obtained azide can then be progressed tothe corresponding triazole by copper-mediated azide-alkyne cycloadditionin the presence of a suitable alkylpropriolate in the presence of a basesuch as DIEA, and a copper compound like CuI, or CuSO₄ in the presenceof sodium ascorbate, similarly to the conditions described for Scheme 1and 2. Finally, the triazole-2-carboxy ester derivatives can beconverted to the corresponding triazole-2-carboxy amides, employingprocedures and conditions similar to those described in detail forScheme 1.

An additional synthetic route to prepare compounds of this invention isdescribed in Scheme 4.

A suitably functionalized alkyl hydrazide bearing a protected hydroxylmoiety can be converted to a 5-alkyl-2-amino thiadazole by heating in asolvent such as toluene in the presence of P₂S₅, similarly to thetransformation described in Scheme 2. Suitable protecting groups for thehydroxyl moiety can be chosen amongst substituted ethers and otherssuitable functional groups known to those skilled in the art, asdetailed in G. M. Wutz, T. W. Greene, “Greene's protective Groups inOrganic Synthesis”, Fourth Edition, John Wiley & Sons, and can beremoved following the transformations and procedures reported therein.Following removal of the selected protecting group, the hydroxyl moietycan then be converted into an azide group employing the trasformationsdescribed in Schemes 1 and 3. The obtained functionalized amide can thenbe progressed to the desired triazole derivatives by employing acopper-mediated azide-alkyne cycloaddition in the presence of a suitablealkylpropriolate to obtain the 2-carboxy ester triazoles, followed byfunctional group manipulation to install the 2-carboxy amide, as alreadydescribed in detail for Schemes 1-3.

An additional synthetic route for the compounds described in thisinvention is described in Scheme 5. A suitable hydroxy alkyne can beprogressed into the corresponding azide by a two-step sequence involvingmesylation or tosylation with the required sulfonyl chloride in thepresence of a base such as TEA or DIEA in a solvent like DCM, followedby displacement with an inorganic azide such as NaN₃ in a polar solventlike DMF. Copper-mediated azide-alkyne cycloaddition in the presence ofa suitable alkyl propiolate can then afford the N-alkyne-2-carboxyestertriazole derivatives, in conditions similar to those already detailedfor Schemes 1-4. The 2-carboxyester triazole derivatives can in turn beprogressed to the corresponding 2-carboxyamides, employing similartransformations and conditions to those described for Schemes 1-4. Afurther copper-mediated azide-alkyne cycloaddion step employing asuitably functionalized azide and in analogous conditions to thosedetailed in Schemes 1-4 can then afford the desired bis-triazoloderivatives.

Non-limiting examples include the following compounds andpharmaceutically acceptable salts thereof.

Example 1:N-(pyridin-3-ylmethyl)-1-[4-(5-{2-[3-(trifluoromethoxy)phenyl]acetamido}-1,3,4-thiadiazol-2-yl)butyl]-1H-1,2,3-triazole-4-carboxamide

Steps 1 to 4

Step 1: 4-cyanobutyl Benzoate

To a solution of benzoic acid (0.543 g, 4.44 mmol) in DMF (5 mL) wasadded K₂CO₃ (1.02 g, 7.41 mmol) and the mixture was stirred at RT for 10minutes. 5-Bromopentanenitrile (0.60 g, 3.7 mmol) was added dropwise andthe reaction was heated in a sealed vial at 85° C. for 2.5 h, then at60° C. for 17 h. The mixture was concentrated under reduced pressure,diluted with water (75 mL), and extracted with EtOAc (2×50 mL). Thecombined organic layers were washed with brine, dried (MgSO₄), filtered,and concentrated under reduced pressure to give the title compound as aclear oil (765 mg, 3.58 mmol, 97%). MS (ES⁺) C₁₂H₁₃NO₂ requires: 203.1,found: 204 [M+H]⁺.

Step 2: 4-(5-amino-1,3,4-thiadiazol-2-yl)butyl Benzoate

To a solution of 4-cyanobutyl benzoate (760 mg, 3.74 mmol) in TFA (10mL) was added hydrazinecarbothioamide (409 mg, 4.49 mmol) and theresulting mixture was stirred at 85° C. for 3 h. The reaction mixturewas allowed to cool to RT and the volatiles were removed under reducedpressure. The residue was dissolved in DCM/MeOH (5 mL, 1/1 v/v),MP-carbonate resin (6 g, 6.06 mmol/g) was added, and the mixture wasstirred for 3 h at RT. The mixture was filtered and concentrated underreduced pressure to give the title compound as a white solid (822 mg,2.96 mmol, 79%). MS (ES⁺) C₁₃H₁₅N₃O₂S requires: 277.1, found: 278[M+H]⁺.

Step 3:4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butylBenzoate

To a solution of 4-(5-amino-1,3,4-thiadiazol-2-yl)butyl benzoate (571mg, 2.06 mmol) in DMF (15 mL) were added2-(3-(trifluoromethoxy)phenyl)acetic acid (544 mg, 2.47 mmol), HOBT (378mg, 2.47 mmol), DIEA (0.45 mL, 2.6 mmol), and EDC.HCl (474 mg, 2.47mmol) and the resulting mixture was stirred at RT for 18 h. The reactionwas slowly poured onto ice water (250 mL) and stirred for 1 h. Themixture was filtered and the white solid was washed with water,saturated NaHCO₃, water, and hexanes to give the title compound as awhite solid (530 mg, 1.10 mmol, 54%). MS (ES⁺) C₂₂H₂₀F₃N₃O₄S requires:479.1, found: 480 [M+H]⁺.

Step 4:N-(5-(4-hydroxybutyl)-1,3,4-thiadiazol-2-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide

To a solution of4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butylbenzoate (527 mg, 1.10 mmol) in THF (7 mL) and water (7 mL) was addedLiOH (2M aq., 5.50 mL, 11.0 mmol) and the resulting mixture was stirredat RT for 5 h. The volatiles were removed under reduced pressure. Theresidue was partitioned between DCM (200 mL) and H₂O (200 mL), and thelayers were separated. The aqueous phase was extracted with DCM (3×100mL) and the organic layers were combined, washed with brine, dried(MgSO₄), filtered, and concentrated under reduced pressure to give thetitle compound as an off white solid (300 mg, 0.799 mmol, 73%). MS (ES⁺)C₁₅H₁₆F₃N₃O₃S requires: 375.1, found: 376 [M+H]⁺.

Steps 5 to 8

Step 5:N-(5-(4-azidobutyl)-1,3,4-thiadiazol-2-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide

To a solution ofN-(5-(4-hydroxybutyl)-1,3,4-thiadiazol-2-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide(297 mg, 0.790 mmol) and DBU (0.179 mL, 1.19 mmol) in THF (5 mL) wasadded DPPA (0.26 mL, 1.2 mmol) dropwise and the resulting mixture wasstirred at 60° C. for 3 h. The volatiles were removed under reducedpressure and the residue was purified via SiO₂ gel chromatography(0-100% EtOAc in hexanes) to give the title compound as a white solid(217 mg, 0.542 mmol, 69%). MS (ES⁺) C₁₅H₁₅F₃N₆O₂S requires: 400.1,found: 401 [M+H]⁺.

Step 6: ethyl1-(4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

To a solution ofN-(5-(4-azidobutyl)-1,3,4-thiadiazol-2-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide(214 mg, 0.534 mmol) in DCM (5 mL) were added DIEA (9.3 μl, 0.053 mmol),AcOH (3.06 μl, 0.053 mmol), ethyl propiolate (0.065 mL, 0.641 mmol), andcopper(I) iodide (5.1 mg, 0.027 mmol) and the resulting mixture wasstirred at RT for 16 h. The reaction was concentrated under reducedpressure, the residue was taken up in MeOH, and the product wasprecipitated by addition of saturated aq. NH₄Cl. The precipitate waswashed with water, hexanes, and dried under reduced pressure to give thetitle compound as a white solid (217 mg, 0.430 mmol, 81%). MS (ES⁺)C₂₀H₂₁F₃N₆O₄S requires: 498.1, found: 499 [M+H]⁺.

Step 7:1-(4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylicacid

To a suspension of ethyl1-(4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylate(211 mg, 0.423 mmol) in THF/H₂O (10 mL, 1/1 v/v) was added LiOH (2 Maq., 1.06 mL, 2.12 mmol) and the resulting mixture was stirred at RT for16 h. The volatiles were removed under reduced pressure, the aqueousphase was brought to pH 2 by the addition of 1N aq. HCl, and theresulting solid product was collected by filtration and dried underreduced pressure to give the title compound as a white solid (193 mg,0.411 mmol, 97%). MS (ES⁺) C₁₈H₁₇F₃N₆O₄S requires: 470.1, found: 471[M+H]⁺.

Step 8:N-(pyridin-3-ylmethyl)-1-(4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of1-(4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylicacid (10 mg, 0.021 mmol) in DMSO (0.1 mL) were added DIEA (8.17 μl,0.0470 mmol), pyridin-3-ylmethanamine (2.3 mg, 0.021 mmol), and HATU(12.1 mg, 0.032 mmol). The resulting mixture was stirred at RT for 16 hand diluted with water. The resulting precipitate was filtered, washedwith water, and dried under reduced pressure. The residue was purifiedby mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1%TFA/MeCN; Gradient: B=30-70%; 12 min; Column: C18) to give the titlecompound as a white solid (3.3 mg, 5.9 μmol, 28%). MS (ES⁺)C₂₄H₂₃F₃N₈O₃S requires: 560.2, found: 561 [M+H]⁺. ¹H NMR (DMSO-d₆) δ:12.70 (br s, 1H), 9.25 (m, 1H), 8.79-8.56 (m, 3H), 8.09 (d, J=7.9 Hz,1H), 7.67 (m, 1H), 7.47 (m, 1H), 7.38-7.31 (m, 2H), 7.28 (d, J=8.7 Hz,1H), 4.54 (d, J=6.0 Hz, 2H), 4.45 (t, J=7.0 Hz, 2H), 3.89 (s, 2H), 3.00(t, J=7.4 Hz, 2H), 1.94-1.87 (m, 2H), 1.68-1.59 (m, 2H).

Example 2:N-Methyl-1-(4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

Prepared as described for Example 1. MS (ES⁺) C₁₉H₂₀F₃N₇O₃S requires:483.1, found: 484 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ: 12.69 (s, 1H),8.54 (s, 1H), 8.44 (q, J=4.5 Hz, 1H), 7.47 (m, 1H), 7.38-7.32 (m, 2H),7.28 (d, J=8.7 Hz, 1H), 4.48-4.40 (m, 2H), 3.89 (s, 2H), 3.00 (t, J=7.6Hz, 2H), 2.75 (d, J=4.9 Hz, 3H), 1.95-1.86 (m, 2H), 1.69-1.58 (m, 2H).

Example 3:1-(4-(5-(2-(3-(Trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

To a suspension ofN-(2,4-dimethoxybenzyl)-1-(4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxamide(prepared as described for Example 1; 14 mg, 0.023 mmol) in DCM (1 mL)was added TFA (0.106 mL, 1.375 mmol) and the resulting mixture wasstirred at RT for 7 h. The reaction was concentrated under reducedpressure and the residue was triturated with aq. NaHCO₃ (10/1 v/vwater/saturated aq. NaHCO₃). The resulting solid was filtered and washedwith water to give the title compound as an off white solid (7.4 mg,0.016 mmol, 69%). MS (ES⁺) C₁₈H₁₈F₃N₇O₃S requires: 469.1, found: 470[M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ: 8.53 (s, 1H), 7.83 (s, 1H), 7.49(m, 1H), 7.38-7.32 (m, 2H), 7.27 (d, J=8.7 Hz, 1H), 4.44 (t, J=6.8 Hz,2H), 3.88 (s, 2H), 3.00 (t, J=7.4 Hz, 2H), 1.95-1.86 (m, 2H), 1.69-1.60(m, 2H).

Example 4:N-Benzyl-1-(5-(5-(2-phenylacetamido)-1,3,4-thiadiazol-2-yl)pentyl)-1H-1,2,3-triazole-4-carboxamide

Prepared as Example 1, using 5-cyanopentyl benzoate instead of4-cyanobutyl benzoate. MS (ES⁺) C₂₅H₂₇N₇O₂S requires: 489.2, found: 490[M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ: 8.08 (s, 1H), 7.49 (br s, 1H),7.42-7.37 (m, 2H), 7.37-7.27 (m, 8H), 4.68-4.59 (m, 2H), 4.37 (t, J=7.0Hz, 2H), 3.98 (s, 2H), 3.02 (t, J=7.4 Hz, 2H), 1.97 (m, 2H), 1.85 (m,2H), 1.44 (m, 2H).

Example 5:N-Benzyl-1-(4-(6-(2-phenylacetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

Steps 1 to 5

Step 1: N-(6-chloropyridazin-3-yl)-2-phenylacetamide

To a mixture of 6-chloropyridazin-3-amine (4.0 g, 31 mmol) and DIEA (6.5mL, 37 mmol) in NMP (40 mL) at 0° C. was added 2-phenylacetyl chloride(4.49 mL, 34.0 mmol) dropwise. The reaction was stirred at 0° C. for 30minutes, allowed to warm to RT over 19 h, and poured onto ice water (500mL). The resulting precipitate was filtered, washed with water and Et₂O(3×20 mL), and dried under reduced pressure to give the title compoundas an off-white solid (3.4 g, 13 mmol, 42%). MS (ES⁺) C₁₂H₁₀ClN₃Orequires: 247.1, found: 248 [M+H]⁺.

Step 2: N-(6-(4-hydroxybut-1-yn-1-yl)pyridazin-3-yl)-2-phenylacetamide

To a solution of N-(6-chloropyridazin-3-yl)-2-phenylacetamide in DMF (4mL) were added TEA (2.0 mL, 14 mmol) and but-3-yn-1-ol (0.306 mL, 4.04mmol), and the mixture was degassed with a stream of N₂ for 5 minutes.Copper(I) iodide (0.038 g, 0.20 mmol) and PdCl₂(PPh₃)₂ (0.071 g, 0.101mmol) were added and the mixture was heated in a sealed vial at 85° C.16 h. The mixture was cooled to RT, the volatiles were removed underreduced pressure, and the residue was purified via silica gelchromatography (0-5% MeOH in DCM) to give the title compound as a yellowsolid (238 mg, 0.846 mmol, 42%). MS (ES⁺) C₁₆H₁₅N₃O₂ requires: 281.1,found: 282 [M+H]⁺.

Step 3: N-(6-(4-hydroxybutyl)pyridazin-3-yl)-2-phenylacetamide

To a flask containing Pd(OH)₂ (20% wt on carbon, 353 mg, 0.252 mmol)under N₂ was added EtOH (10 mL) followed byN-(6-(4-hydroxybut-1-yn-1-yl)pyridazin-3-yl)-2-phenylacetamide (236 mg,0.839 mmol). The flask was evacuated, filled with H₂, and the mixturestirred at RT under a hydrogen atmosphere for 3.5 h. The flask wasevacuated and filled with N₂. The suspension was filtered through a padof Celite®, rinsed with MeOH and DCM, and the filtrate was concentratedunder reduced pressure to give the title compound as a yellow solid (210mg, 0.735 mmol, 88%). MS (ES⁺) C₁₆H₁₉N₃O₂ requires: 285.2, found: 286[M+H]⁺.

Step 4: N-(6-(4-azidobutyl)pyridazin-3-yl)-2-phenylacetamide

Prepared as described for Example 1, step 5. MS (ES⁺) C₁₆H₁₈N₆Orequires: 310.1, found: 311 [M+H]⁺.

Steps 5 to 7

Prepared as described for Example 1, steps 5-to 7;

Step 5: ethyl1-(4-(6-(2-phenylacetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

MS (ES⁺) C₂₁H₂₄N₆O₃ requires: 408.2, found: 409 [M+H]⁺.

Step 6:1-(4-(6-(2-phenylacetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylicacid

MS (ES⁺) C₁₉H₂₀N₆O₃ requires: 380.2, found: 381 [M+H]⁺.

Step 7:N-benzyl-1-(4-(6-(2-phenylacetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

MS (ES⁺) C₂₆H₂₇N₇O₂ requires: 469.2, found: 470 [M+H]⁺. ¹H NMR (600 MHz,DMSO-d₆) δ: 11.23 (br s, 1H), 9.02 (d, J=5.3 Hz, 1H), 8.57 (s, 1H), 8.19(d, J=9.1 Hz, 1H), 7.53 (d, J=9.1 Hz, 1H), 7.37-7.28 (m, 8H), 7.27-7.18(m, 2H), 4.49-4.40 (m, 4H), 3.76 (s, 2H), 2.88 (t, J=7.6 Hz, 2H),1.94-1.83 (m, 2H), 1.69-1.59 (m, 2H).

Example 6:N-(2-methoxyethyl)-5-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1,3,4-thiadiazole-2-carboxamide

Steps 1 to 3

Step 1: Ethyl 2-oxo-2-(2-pent-4-ynoylhydrazinyl)acetate

To a solution of pent-4-ynehydrazide (560 mg, 5.00 mmol) and TEA (530mg, 5.25 mmol) in DCM/THF (25 mL/5 mL) at 0° C. was slowly added ethyl2-chloro-2-oxoacetate (717 mg, 5.25 mmol). The resulting mixture wasstirred for 30 minutes while warming to RT, then concentrated underreduced pressure. The residue was triturated with EtOAc (20 mL),filtered, and the filtrate was concentrated under reduced pressure togive the title compound. MS (ES⁺) C₉H₁₂N₂O₄, requires: 212.08, found:213 [M+H]⁺.

Step 2: Ethyl 5-(but-3-yn-1-yl)-1,3,4-thiadiazole-2-carboxylate

To a solution of ethyl 2-oxo-2-(2-pent-4-ynoylhydrazinyl)acetate (1.0 g,5.0 mmol) in toluene (50 mL) heated at 70° C. was added P₂S₅ (1.11 g,5.0 mmol) portionwise, and the resulting mixture was stirred for 30minutes at 70° C. The mixture was cooled to RT, filtered, and the filtercake was washed with DCM (20 mL). The filtrate was concentrated underreduced pressure and the residue was purified by SiO₂ gel chromatography(20% EtOAc in hexanes) to give the title compound as a yellow solid (532mg, 50%). MS (ES⁺) C₉H₁₀N₂O₂S, requires: 210.05, found: 211[M+H]⁺. ¹HNMR (500 MHz, CDCl₃) δ 4.54 (m, 2H), 3.44 (t, J=6.9 Hz, 2H), 2.75 (td,J=7.0, 2.7 Hz, 2H), 2.13 (t, J=2.6 Hz, 1H), 1.49 (m, 3H).

Step 3:5-(but-3-ynyl)-N-(2-methoxyethyl)-1,3,4-thiadiazole-2-carboxamide

A mixture of ethyl 5-(but-3-ynyl)-1,3,4-thiadiazole-2-carboxylate (300mg, 1.43 mmol) and 2-methoxyethanamine (2 mL) was heated at 80° C. in asealed tube for 2 h. The mixture was then cooled to RT, diluted withwater (10 mL), and extracted with EtOAc (2×20 mL). The combined organiclayers were washed with brine (50 mL), dried (Na₂SO₄), and concentratedunder reduced pressure to give the title compound as a yellow solid (310mg, 91%). MS (ES⁺) C₁₀H₁₃N₃O₂S requires: 239, found: 240[M+H]⁺.

Step 4: N-(6-iodopyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide

A mixture of 6-iodopyridazin-3-amine hydrogen iodide salt (1.05 g, 3.00mmol), 2-(3-(trifluoromethoxy)phenyl)acetic acid (792 m g, 3.6 mmol),propylphosphonic anhydride (2.86 g, 4.5 mmol, 50% wt in EtOAc), andDIPEA (1.16 g, 9 mmol) in DMF (10 mL) was stirred at RT for 16 h. Themixture was then poured onto H₂O (30 mL) and extracted with EtOAc (2×30mL). The combined organic layers were washed with brine (50 mL), dried(Na₂SO₄), and concentrated under reduced pressure. The residue waspurified by SiO₂ gel chromatography (30% EtOAc in hexanes) to give thetitle compound as a white solid (1.1 g, 87%). MS (ES⁺) C₁₃H₉F₃IN₃O₂requires: 423, found: 424 [M+H]⁺.

Steps 5 to 6

Step 5:N-(2-methoxyethyl)-5-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)but-3-ynyl)-1,3,4-thiadiazole-2-carboxamide

A mixture ofN-(6-iodopyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide (120mg, 0.280 mmol),5-(but-3-ynyl)-N-(2-methoxyethyl)-1,3,4-thiadiazole-2-carboxamide (105mg, 0.430 mmol), Pd(PPh₃)₂Cl₂ (20 mg, 0.028 mmol), CuI (11 mg, 0.056mmol), and TEA (85 mg, 0.84 mmol) in DMF (3 mL) was heated at 30° C. for16 h. The mixture was then diluted with water (10 mL) and extracted withDCM/MeOH (10/1 v/v, 3×20 mL). The combined organic layers were dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The residuewas purified by preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1%TFA/MeCN; Gradient: B=30-70%; 12 min; Column: C18) to afford the titlecompound as a white solid (80 mg, 54%). MS (ES⁺) C₂₃H₂₁F₃N₆O₄S requires:534, found: 535[M+H]⁺.

Step 6:N-(2-methoxyethyl)-5-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1,3,4-thiadiazole-2-carboxamide

To a flask containing 10% Pd—C (10 mg) under N₂ was added THF (1 mL)followed byN-(2-methoxyethyl)-5-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)but-3-ynyl)-1,3,4-thiadiazole-2-carboxamide(30 mg, 0.056 mmol). The flask was evacuated and filled with H₂, and themixture stirred at 30° C. under a H₂ atmosphere for 3 h. The flask wasevacuated and filled with N₂, the suspension was filtered through a padof Celite®, and the filtrate concentrated under reduced pressure. Theresidue was purified by preparative HPLC (Mobile phase: A=0.1% TFA/H₂O,B=0.1% TFA/MeCN; Gradient: B=30-70%; 12 min; Column: C18) to afford thetitle compound as a white solid (25 mg, 78%). MS (ES⁺) C₂₃H₂₅F₃N₆O₄Srequires: 538, found: 539[M+H]⁺; ¹H NMR (400 MHz, DMSO) δ 11.32 (s, 1H),9.11 (t, J=5.4 Hz, 1H), 8.19 (d, J=9.2 Hz, 1H), 7.57 (d, J=9.1 Hz, 1H),7.47 (m, 1H), 7.40-7.33 (m, 2H), 7.26 (d, J=7.8 Hz, 1H), 3.85 (s, 2H),3.51-3.39 (m, 4H), 3.25 (s, 3H), 3.18 (t, J=6.1 Hz, 2H), 2.90 (t, J=6.8Hz, 2H), 1.83-1.71 (m, 4H).

Example 7:N-(2-methoxyethyl)-5-(4-(4-(3-(trifluoromethyl)benzylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1,3,4-thiadiazole-2-carboxamide

Steps 1 to 6

Step 1: 5-(benzyloxy)pentanoic acid

To a solution of tetrahydro-2H-pyran-2-one (5.0 g, 50 mmol) in toluene(50 mL) were added KOH (15.8 g, 28.2 mmol) and benzylbromide (17.8 mL,150 mmol), and the mixture was stirred at 125° C. for 16 h. The solutionwas cooled to RT and diluted with ice/H₂O (70 mL). The organic layer wasseparated and the aqueous layer was washed with MTBE (3×30 mL). Theaqueous layer was then cooled to 0° C. and the pH was adjusted to 3-4 bythe addition of concentrated aq. HCl (15 mL) and 6 N aq. HCl (8 mL). Themixture was extracted with EtOAc (4×50 mL) and the combined organiclayers were washed with brine (20 mL), dried (Na₂SO₄), and concentratedunder reduced pressure to give 5-(benzyloxy)pentanoic acid as a lightyellow oil (10 g, 96%). MS (ES⁺) C₁₂H₁₆O₃ requires: 208, found:209[M+H]⁺.

Step 2: methyl 5-(benzyloxy)pentanoate

To a solution of 5-(benzyloxy)pentanoic acid (1.0 g, 4.8 mmol) in MeOH(40 mL) at 0° C. was slowly added SOCl₂ (0.39 mL, 5.3 mmol) and themixture was stirred at RT for 1 h. The mixture was then treated withsaturated aq. NaHCO₃ (5 mL), the volatiles were removed under reducedpressure, and the aqueous layer was extracted with DCM (3×10 mL). Thecombined organic layers were washed with brine (5 mL), dried (Na₂SO₄),and concentrated under reduced pressure to afford methyl 5-(benzyloxy)pentanoate as a light yellow oil (1.0 g, 94%). MS (ES⁺) C₁₃H₁₈O₃requires: 222, found: 223[M+H]⁺.

Step 3: 5-(benzyloxy)pentanehydrazide

A mixture of methyl 5-(benzyloxy)pentanoate (1.0 g, 4.5 mmol) and NH₂NH₂(35% wt. solution in H₂O, 1.3 mL, 14 mmol) in MeOH (15 mL) was heated atreflux in a pressure safe vial for 18 h. The mixture was cooled to RTand the volatiles were removed under reduced pressure. The residue wastaken up in toluene (2×5 mL) and concentrated again. The resulting solidwas triturated with hexanes (2×5 mL) and filtered to give5-(benzyloxy)pentanehydrazide as a white solid (840 mg, 84%). MS (ES⁺)C₁₂H₁₈N₂O₂ requires: 222, found: 223[M+H]⁺.

Step 4: ethyl 2-(2-(5-(benzyloxy)pentanoyl)hydrazinyl)-2-oxoacetate

To a solution of 5-(benzyloxy)pentanehydrazide (500 mg, 2.25 mmol) andTEA (0.627 mL, 4.50 mmol) in DCM (5.0 mL) at 0° C. was added ethyl2-chloro-2-oxoacetate (0.448 mL, 4.00 mmol), and the resulting mixturewas stirred at RT for 30 minutes. The volatiles were removed underreduced pressure to give the title compound as a white solid (800 mg,100%). MS (ES⁺) C₁₆H₂₂N₂O₅ requires: 322, found: 323 [M+H]⁺.

Step 5: ethyl 5-(4-(benzyloxy)butyl)-1,3,4-thiadiazole-2-carboxylate

To a mixture of ethyl2-(2-(5-(benzyloxy)pentanoyl)hydrazinyl)-2-oxoacetate (400 mg, 2.30mmol) in toluene (5 mL) at 60° C. was added P₂O₅ (500 mg, 2.3 mmol). Thereaction mixture was stirred at 60° C. for 15 minutes, cooled to RT, andpartitioned between saturated aq. NaHCO₃ (30 mL) and EtOAc (50 mL). Theorganic layer was collected, washed with brine (5 mL), dried (Na₂SO₄),and concentrated under reduced pressure. The residue was purified bySiO₂ gel chromatography (5% to 20% EtOAc in hexanes) to give the titlecompound as a yellow oil (1.3 g, 48%). MS (ES⁺) C₁₆H₂₀N₂O₃S requires:320, found: 321 [M+H]⁺.

Step 6: ethyl 5-(4-hydroxybutyl)-1,3,4-thiadiazole-2-carboxylate

To a solution of ethyl5-(4-(benzyloxy)butyl)-1,3,4-thiadiazole-2-carboxylate (1.0 g, 3.1 mmol)in DCM (30 mL) was added anhydrous FeCl₃ (2.0 g, 13 mmol) portionwise.The reaction mixture was stirred at RT for 25 minutes, a further aliquotof anhydrous FeCl₃ (1.0 g, 6.3 mmol) was added, and the mixture wasstirred for an additional 10 minutes. The mixture was then treated withsaturated aq. NH₄Cl (10 mL), the layers were separated, and the aqueousphase was extracted with DCM/MeOH=10/1 v/v (3×50 mL). The combinedorganic layers were washed with brine (10 mL), dried (Na₂SO₄), andconcentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 2% MeOH in DCM) to give the title compound asa brown oil (730 mg, 100%). MS (ES⁺) C₉H₁₄N₂O₃S requires: 230, found:231 [M+H]⁺.

Steps 7 to 10

Step 7: 5-(4-(Methylsulfonyloxy)butyl)-1,3,4-thiadiazole-2-carboxylate

To a solution of ethyl5-(4-hydroxybutyl)-1,3,4-thiadiazole-2-carboxylate (2.30 g, 10.0 mmol;prepared as described for Example 6, step 3) and Et₃N (3.0 g, 30 mmol)in DCM (25 mL) at 0° C. was added MsCl (1.2 mL, 15.0 mmol) in DCM (5 mL)dropwise. The reaction mixture was stirred at 0° C. for 10 minutes, thenat RT for 20 minutes. The mixture was then diluted with H₂O (50 mL) andextracted with DCM (100 mL). The organic layer was dried (Na₂SO₄),filtered, and concentrated under reduced pressure to give the titlecompound as an oil (3.0 g, 97%). MS (ES⁺) C₁₀H₁₆N₂O₅S₂ requires: 308,found: 309 [M+H]⁺.

Step 8: Ethyl 5-(4-azidobutyl)-1,3,4-thiadiazole-2-carboxylate

To a solution of ethyl5-(4-(methylsulfonyloxy)butyl)-1,3,4-thiadiazole-2-carboxylate (3.0 g,9.7 mmol) in DMF (15 mL) was added NaN₃ (1.26 g, 19.4 mmol) and thereaction mixture was stirred at 80° C. for 2 h. The mixture was thencooled to RT, poured onto ice water (100 mL) and extracted with DCM(2×100 mL). The combined organic layers were washed with brine (100 mL),dried (Na₂SO₄), and concentrated under reduced pressure to give thetitle compound as an oil (2.45 g, 96%). MS (ES⁺) C₉H₁₃N₅O₂S requires:255, found: 256 [M+H]⁺.

Step 9: Ethyl5-(4-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)butyl)-1,3,4-thiadiazole-2-carboxylate

To a solution of ethyl 5-(4-azidobutyl)-1,3,4-thiadiazole-2-carboxylate(2.45 g, 9.60 mmol) in t-BuOH (15 mL) and H₂O (15 mL) were addedCuSO₄.5H₂O (490 mg, 2.65 mmol) and L-(+)-ascorbic acid (980 mg, 5.57mmol). The reaction mixture was stirred at RT for 3 h, diluted withwater (100 mL), and extracted with EtOAc (2×100 mL). The combinedorganic layers were washed with brine (100 mL), dried (Na₂SO₄), andconcentrated under reduced pressure to give the title compound as alight yellow solid (2.2 g, 5.8 mmol, 60%). MS (ES⁺) C₁₆H₂₃N₅O₄Srequires: 381, found: 382 [M+H]⁺.

Step 10:1-(4-(5-(Ethoxycarbonyl)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylicacid

To a solution of ethyl5-(4-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)butyl)-1,3,4-thiadiazole-2-carboxylate(3.2 g, 5.8 mmol) in DCM (10 mL) was added TFA (5.0 mL). The reactionmixture was stirred at RT for 16 h then concentrated under reducedpressure. CH₃CN (10 mL) was added resulting in the formation of aprecipitate, which was filtered off to give the title compound as alight yellow solid (1.30 g, 70%). MS (ES⁺) C₁₂H₁₅N₅O₄S requires: 325,found: 326 [M+H]⁺.

Steps 11 to 12

Step 11: Ethyl5-(4-(4-(3-(trifluoromethyl)benzylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1,3,4-thiadiazole-2-carboxylate

To a solution of1-(4-(5-(ethoxycarbonyl)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylicacid (1.0 g, 3.1 mmol) and (3-(trifluoromethyl)phenyl)methanamine (592mg, 3.38 mmol) in DMF (6.0 mL) were added HATU (1.75 g, 4.61 mmol) andDIEA (990 mg, 7.70 mmol). The reaction mixture was stirred at RT for 2 hthen diluted with H₂O (20 mL). The solid was collected by filtration togive the title compound as a light yellow solid (1.35 g, 91%). MS (ES⁺)C₂₀H₂₁F₃N₆O₃S requires: 482, found: 483 [M+H]⁺.

Step 12:N-(2-Methoxyethyl)-5-(4-(4-(3-(trifluoromethyl)benzylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1,3,4-thiadiazole-2-carboxamide

To a suspension of ethyl5-(4-(4-(3-(trifluoromethyl)benzylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1,3,4-thiadiazole-2-carboxylate(96 mg, 0.20 mmol) in MeOH (1.0 mL) was added 2-methoxyethanamine (0.05mL, 0.7 mmol) and the reaction mixture was heated in a sealed tube at80° C. for 2 h. The mixture was cooled to RT, the solid was filtered offand washed with MeOH (5.0 mL) to give the title compound as a whitesolid (82 mg, 77%). MS (ES⁺) C₂₁H₂₄F₃N₇O₃S requires: 511, found: 512[M+H]⁺; ¹H NMR (400 MHz, DMSO) δ 9.22 (t, J=6.1 Hz, 1H), 9.13 (t, J=5.2Hz, 1H), 8.63 (s, 1H), 7.46 (m, 1H), 7.34 (d, J=7.7 Hz, 1H), 7.29 (s,1H), 7.24 (d, J=7.9 Hz, 1H), 4.61-4.35 (m, 4H), 3.54-3.41 (m, 4H), 3.25(s, 3H), 2.01-1.87 (m, 2H), 1.79-1.65 (m, 2H).

Example 8: Tert-butyl4-((4-(4-(4-(3-(trifluoromethoxy)benzylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazol-1-yl)methyl)piperidine-1-carboxylate

Steps 1 to 5

Step 1: Hex-5-ynyl 4-methylbenzenesulfonate

To a solution of hex-5-yn-1-ol (1 g, 10 mmol) in DCM (20 ml) were addedTEA (1.24 g, 12.2 mmol) and 4-methylbenzene-1-sufonyl chloride (1.9 g,10 mmol). The resulting mixture was stirred at RT for 1 h andconcentrated under reduced pressure to give the title compound as yellowoil (2.5 g, 97%). MS (ES⁺) C₁₃H₁₆O₃S required: 252, found: 253 [M+H]⁺.

Step 2: 6-Azidohex-1-yne

To a solution of hex-5-ynyl 4-methylbenzenesulfonate (1.0 g, 3.9 mmol)in DMF (10 mL) and water (10 mL) was added NaN₃ (525 mg, 7.90 mmol). Theresulting mixture was stirred at 80° C. for 12 h, then cooled to RT andpartitioned between Et₂O (20 mL) and water (20 mL). The organic layerwas collected, washed with water (30 mL), brine (30 mL), dried (Na₂SO₄),filtered, and concentrated under reduced pressure at 0° C. to give thetitle compound as a yellow oil (460 mg, 94%). MS (ES⁺) C₆H₉N₃ requires:123, found: 124 [M+H]⁺.

Step 3: Methyl 1-(hex-5-ynyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of 6-azidohex-1-yne (488 mg, 3.90 mmol) in ^(t)BuOH (10mL) and water (10 mL) were added methyl propiolate (499 mg, 5.90 mmol),CuSO₄.5H₂O (100 mg, 0.400 mmol) and sodium ascorbate (200 mg, 1.00mmol). The resulting mixture was stirred at RT for 1 h, then partitionedbetween EtOAc (20 mL) and water (20 mL). The organic layer wascollected, washed with water (30 mL), sat. NH₄Cl (3×30 mL), brine (30mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressureto give the title compound as yellow solid (500 mg, 61%). MS (ES⁺)C₁₀H₁₃N₃O₂ requires: 207, found: 208 [M+H]⁺.

Step 4: 1-(hex-5-ynyl)-1H-1,2,3-triazole-4-carboxylic acid

To a solution of methyl 1-(hex-5-ynyl)-1H-1,2,3-triazole-4-carboxylate(500 mg, 2.40 mmol) in MeOH (10 mL) and water (10 mL) was added LiOH.H₂O(250 mg, 6.00 mmol) and the resulting mixture was stirred at RT for 2 h.The reaction was partitioned between EtOAc (20 mL) and water (20 mL),the organic layer was collected, washed with water (30 mL), brine (30mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressureto give the title compound as yellow solid (450 mg, 96%). MS (ES⁺)C₉H₁₁N₃O₂ requires: 193, found: 194 [M+H]⁺.

Step 5:1-(Hex-5-ynyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of 1-(hex-5-ynyl)-1H-1,2,3-triazole-4-carboxylic acid (235mg, 1.22 mmol) in DCM (15 mL) were added3-(trifluoromethoxy)phenyl)methanamine (255 mg, 1.34 mmol), HATU (695mg, 1.83 mmol), and DIEA (472 mg, 3.66 mmol), and the resulting mixturewas stirred at RT for 12 h. The mixture was partitioned between DCM (20mL) and water (20 mL), the organic layer was collected, washed withwater (3×30 mL), brine (30 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0 to 20% MeOH in DCM) to give the title compound asyellow solid (300 mg, 67%). MS (ES⁺) C₁₇H₁₇F₃N₄O₂ requires: 366, found:367 [M+H]⁺.

Steps 6 to 7

Step 6: Tert-butyl 4-(azidomethyl)piperidine-1-carboxylate

To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate(1.0 g, 4.6 mmol) in DCM (20 mL) at 0° C., were added TEA (0.67 g, 6.9mmol) and methylsulfonyl chloride (0.57 g, 5.0 mmol). The mixture wasstirred at 0° C. for 0.5 h, then diluted with water (20 mL). The organiclayer was collected and concentrated under reduced pressure. The residuewas immediately taken up in DMF (10 mL) and NaN₃ (330 mg, 5.0 mmol) wasadded. The mixture was stirred at 80° C. for 2 h, cooled to RT, andextracted with EtOAc (3×20 mL). The combined organic layers were washedwith brine, dried (Na₂SO₄), filtered, and concentrated under reducepressure to afford the title compound as a colorless oil (0.9 g, 80%).¹H NMR (500 MHz, CDCl₃) δ 4.15-4.11 (m, 2H), 3.20-3.18 (d, J=6 Hz, 2H),2.72-2.66 (m, 2H), 1.74-1.70 (m, 3H), 1.46 (s, 9H), 1.18-1.14 (m, 2H).

Step 7: Tert-butyl4-((4-(4-(4-(3-(trifluoromethoxy)benzylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazol-1-yl)methyl)piperidine-1-carboxylate

To a solution of1-(hex-5-ynyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide(50 mg, 0.14 mmol) in ^(t)BuOH (1.5 ml) and water (1.5 ml) were addedCuSO₄ (10 mg, 0.06 mmol), sodium ascorbate (20 mg) and tert-butyl4-(azidomethyl)piperidine-1-carboxylate (49 mg, 0.21 mmol) and themixture was stirred at RT for 1 h. The volatiles were removed underreduced pressure and the residue was purified by preparative HPLC(Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=30-70%; 12min; Column: C18) to give the title compound as a white solid (25 mg,30%). ¹H NMR (500 MHz, CDCl₃) δ 8.07 (s, 1H), 7.55 (m, 1H), 7.39-7.20(m, 3H), (bd, J=8.0 Hz, 1H), 4.61 (d, J=6.0 Hz, 2H), 4.45 (t, J=6.8 Hz,2H), 4.19 (d, J=7.2 Hz, 2H), 4.13-4.08 (m, 2H), 2.78-2.75 (t, J=7.6 Hz,2H), 2.70-2.64 (m, 2H), 2.08-1.98 (m, 3H), 1.80-1.76 (m, 1H), 1.60-1.55(m, 2H), 1.45 (s, 9H), 1.28-1.15 (m, 3H). MS (ES⁺) C₂₈H₃₇F₃N₈O₄requires: 606, found: 607 [M+H]⁺.

Example 9:1-(4-(4-(Methylsulfonamidomethyl)-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

Steps 1 to 5

Step 1: 4-Hydroxybutyl Benzoate

To a solution of butane-1,4-diol (7.44 ml, 84.0 mmol) and DIEA (4.70 ml,27.0 mmol) in MeCN (180 ml) at 0° C. was added dropwise a solution ofbenzoyl chloride (3.13 ml, 27.0 mmol) in MeCN (10 ml), at such a rate tokeep the reaction mixture between 0-5° C. The mixture was stirred for anadditional 15 minutes at 0° C., then warmed to RT, stirred for 16 h, andconcentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (20% EtOAC in hexanes) to give the title compound asa colorless oil (4.82 g, 92%). MS (ES⁺) C₁₁H₁₄O₃ requires: 194, found:195 [M+H]⁺.

Step 2: 4-(Methylsulfonyloxy)butyl Benzoate

To a solution of 4-hydroxybutyl benzoate (5.0 g, 18 mmol) and TEA (3.7g, 36.8 mmol) in DCM (20 ml) was added dropwise MsCl (2.5 g, 22 mmol) asa solution in DCM (10 ml). The mixture was stirred at RT for 30 minutes,diluted with water (30 ml), and extracted with DCM (50 ml). The organiclayer was concentrated under reduced pressure to afford4-(methylsulfonyloxy)butyl benzoate as a colorless oil (5.2 g, 98%). MS(ES⁺) C₁₂H₁₆O₅S requires: 273, found: 274 [M+H]⁺.

Step 3: 4-Azidobutyl Benzoate

To a solution of 4-(methylsulfonyloxy)butyl benzoate (3.0 g, 11.0 mmol)in DMF (15 ml) was added NaN₃ (1.35 g, 22.1 mmol) and the mixture wasstirred at 80° C. for 16 h. The mixture was then cooled to RT, dilutedwith water (30 mL) and extracted with EtOAc (50 mL). The organic layerwas concentrated under reduced pressure to afford 4-azidobutyl benzoateas a yellow oil (3 g, 98%). MS (ES⁺) C₁₁H₁₃N₃O₂ requires: 219, found:220 [M+H]⁺.

Step 4: Tert-butyl1-(4-(benzoyloxy)butyl)-1H-1,2,3-triazole-4-carboxylate

To a mixture of 4-azidobutyl benzoate (5.0 g, 23 mmol) in ^(t)BuOH/H₂O(20 ml, 1/1 v/v), tert-butyl propiolate (2.90 g, 22.8 mmol) andL-(+)-Ascorbic acid (1.0 g, 5.7 mmol) was added CuSO₄.5H₂O (2.0 g, 13mmol). The mixture was stirred at RT for 16 h and concentrated underreduced pressure. The residue was taken up in water (50 ml) and themixture was stirred for 15 minutes at RT. The resulting solid wascollected by filtration to afford the title compound as a white solid(6.5 g, 83%). MS (ES⁺) C₁₈H₂₃N₃O₄ requires: 345.2, found: 346 [M+H]⁺.

Step 5: 1-(4-(Benzoyloxy)butyl)-1H-1,2,3-triazole-4-carboxylic acid

A mixture of tert-butyl1-(4-(benzoyloxy)butyl)-1H-1,2,3-triazole-4-carboxylate (5.0 g, 15 mmol)in TFA/DCM (40 ml, 1/1 v/v) was stirred at RT for 3 h and thenconcentrated under reduced pressure. The residue was taken up in water(30 ml) and the mixture was stirred for 15 minutes at RT. The resultingsolid was collected by filtration and crystallized from MeCN/H₂O toafford the title compound as a white solid (3.8 g, 90%). MS (ES⁺)C₁₄H₁₅N₃O₄ requires: 289.1, found: 290 [M+H]⁺.

Steps 6 to 9

Step 6:4-(4-(3-(Trifluoromethoxy)benzylcarbamoyl)-1H-1,2,3-triazol-1-yl)butylBenzoate

A mixture of 1-(4-(benzoyloxy)butyl)-1H-1,2,3-triazole-4-carboxylic acid(1.0 g, 3.5 mmol), (3-(trifluoromethoxy)phenyl)methanamine (0.66 g, 3.5mmol), HATU (1.9 g, 5.0 mmol) and DIPEA (1.30 g, 10.5 mmol) in DMF (10ml) was stirred at RT for 16 h. The residue was taken up in water (100ml) and the mixture was stirred for 15 minutes at RT. The resultingsolid was filtered to give the title compound as a white solid (1.0 g,62%). MS (ES⁺) C₂₂H₂₁F₃N₄O₄ requires: 462.2, found: 463 [M+H]⁺.

Step 7:1-(4-hydroxybutyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of4-(4-(3-(trifluoromethoxy)benzylcarbamoyl)-1H-1,2,3-triazol-1-yl)butylbenzoate (1.0 g, 2.2 mmol) and LiOH.H₂O (0.27 g, 6.6 mmol) in THF/H₂O(10 ml, 1/1 v/v) was stirred at RT for 16 h. The reaction mixture wasthen partitioned between EtOAc (50 ml) and water (50 ml). The organiclayer was collected and concentrated under reduced pressure to give thetitle compound as a white solid (600 mg, 77%). MS (ES⁺) C₁₅H₁₇F₃N₄O₃requires: 358.1, found: 359 [M+H]⁺.

Step 8:1-(4-azidobutyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of1-(4-hydroxybutyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide(600 mg, 1.68 mmol) and TEA (340 mg, 3.36 mmol) in DCM (5 ml) was addeddropwise a solution of MsCl (240 mg, 2.10 mmol) in DCM (5 ml). Themixture was stirred at RT for 30 minutes, then diluted with water (10ml) and extracted with DCM (20 ml). The organic layer was concentratedunder reduced pressure. The residue was taken up in DMF (3 ml), NaN₃(110 mg, 1.68 mmol) was added and the mixture was stirred at 80° C. for1 h, then cooled to RT. The residue was taken up in water (20 ml) andthe mixture was stirred for 15 minutes at RT. The resulting solid wascollected by filtration to give the title compound as a white solid (600mg, 93%). MS (ES⁺) C₁₅H₁₆F₃N₇O₂ requires: 383.1, found: 384 [M+H]⁺.

Step 9: Tert-butyl(1-(4-(4-(3-(trifluoromethoxy)benzylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazol-4-yl)methylcarbamate

A mixture of1-(4-Azidobutyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide(100 mg, 0.26 mmol), tert-butyl prop-2-ynylcarbamate (40 mg, 0.26 mmol),L-(+)-ascorbic acid (40 mg, 0.23 mmol) and CuSO₄.5H₂O (20 mg, 0.12 mmol)in ^(t)BuOH/H₂O (3 ml, 1/1 v/v) was stirred at RT for 16 h andconcentrated under reduced pressure. The residue was taken up in water(10 ml) and the mixture was stirred for 15 minutes at RT. The resultingsolid was collected by filtration to give the title compound as a whitesolid (100 mg, 71%). MS (ES⁺) C₂₃H₂₉F₃N₈O₄ requires: 538.2, found: 539[M+H]⁺.

Steps 10 to 11

Step 10:1-(4-(4-(Aminomethyl)-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

A solution of tert-butyl(1-(4-(4-(3-(trifluoromethoxy)benzylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazol-4-yl)methylcarbamate(100 mg, 0.19 mmol) in TFA/DCM (3 ml, 1/1 v/v) was stirred at RT for 3 hand concentrated under reduced pressure. The residue was taken up inwater (100 ml) and the mixture was stirred for 15 minutes at RT. Theresulting solid was collected by filtration to give the title compoundas a white solid (70 mg, 86%). MS (ES⁺) C₁₈H₂₁F₃N₈O₂ requires: 438.2,found: 439 [M+H]⁺.

Step 11:1-(4-(4-(methylsulfonamidomethyl)-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of1-(4-(4-(aminomethyl)-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide(70 mg, 0.16 mmol) in DCM (3 ml) were added TEA (48 mg, 0.48 mmol) andmethanesulfonyl chloride (36.7 mg, 0.32 mmol). The mixture was stirredat RT for 3 h and concentrated under reduced pressure. The residue wastaken up in water (10 ml) and the mixture was stirred for 15 minutes atRT. The resulting solid was collected by filtration to give the titlecompound as a white solid (37 mg, 45%). MS (ES⁺) C₁₉H₂₃F₃N₈O₄S requires:516, found: 517 [M+H]⁺. ¹H NMR (500 MHz, DMSO) δ 9.21 (t, J=8.0, 1H),8.60 (s, 1H), 8.01 (s, 1H), 7.51-7.40 (m, 2H), 7.35-7.20 (m, 3H),4.50-4.32 (m, 6H), 4.10 (d, J=7.5, 2H), 2.88 (s, 3H), 1.78-1.73 (m, 4H).

Example 157:N-methyl-1-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

Steps 1 to 3

Step 1: tert-butyl 1-(but-3-ynyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of 4-azidobut-1-yne (20 g, 0.21 mol), t-butyl propiolate (26.5g, 0.21 mol), L-(+)-ascorbic acid (8.0 g, 46 mmol), and CuSO₄ (4.0 g, 25mmol) in 1:1 v: v t-BuOH/H₂O (400 ml) was stirred at RT for 16 h, thenconcentrated under reduced pressure. Water (200 ml) was added, and themixture was extracted with EtOAc (3×300 mL). The combined organic layerswere concentrated under reduced pressure to afford a yellow solid. Thesolid was washed with petroleum ether to give the title compound as awhite solid (25 g, 54%). MS (ES⁺) C₁₁H₁₅N₃O₂ requires: 221, found: 222[M+H]⁺.

Step 2: tert-butyl1-(4-(6-aminopyridazin-3-yl)but-3-ynyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of tert-butyl 1-(but-3-ynyl)-1H-1,2,3-triazole-4-carboxylate(15 g, 68 mmol), 6-iodopyridazin-3-amine (15 g, 68 mmol), Pd(PPh₃)₂Cl₂(4.8 g, 6.8 mmol), CuI (1.3 g, 6.8 mmol), and TEA (34.2 g, 339 mmol) in300 mL of anhydrous THF was stirred at 60° C. under N₂ for 16 h, thenallowed cool to RT. DCM/MeOH (500 mL of a 10:1 v: v mixture) was added,the mixture was filtered and the filtrate concentrated under reducedpressure to give a yellow oil. The oil was purified by SiO₂ gelchromatography (0% to 9% MeOH in DCM) to give the title compound as ayellow solid (18.0 g, 84%). MS (ES⁺) C₁₅H₁₈N₆O₂ requires: 314, found:315 [M+H]⁺.

Step 3: tert-butyl1-(4-(6-aminopyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of tert-butyl1-(4-(6-aminopyridazin-3-yl)but-3-ynyl)-1H-1,2,3-triazole-4-carboxylate(3.5 g, 11 mmol), Raney Ni (300 mg) and MeOH (250 ml) was evacuated andrefilled with hydrogen, then stirred under an atmosphere of H₂ at 1 atmfor 16 h. The mixture was filtered, and the filtrate concentrated underreduced pressure to give a yellow solid. The solid was purified by SiO₂gel chromatography (0% to 9% MeOH in DCM) to give the title compound asa yellow solid (3.17 g, 89%). MS (ES⁺) C₁₅H₂₂N₆O₂ requires: 318, found:319 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.67 (s, 1H), 7.13 (d, J=9.0 Hz,1H), 6.71 (d, J=9.0 Hz, 1H), 6.15 (s, 2H), 4.52-4.37 (m, 2H), 2.69 (t,J=7.6 Hz, 2H), 1.96-1.79 (m, 2H), 1.65-1.42 (m, 11H).

Steps 4 to 6

Step 4: tert-butyl1-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

To a suspension of tert-butyl1-(4-(6-aminopyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylate (80mg, 0.25 mmol), pyridine (0.101 mL, 1.25 mmol) and2-(3-(trifluoromethoxy)phenyl)acetic acid (83 mg, 0.37 mmol) was addedT3P® (50 wt. %, 795 mg, 1.25 mmol) and the resulting mixture was stirredat 80° C. for 1 h and then RT for 12 h. The reaction was concentratedunder reduced pressure and the residue was purified by SiO₂ gelchromatography (0% to 15% MeOH in DCM with 1% NH₄OH) to give the titlecompound as an orange solid (136 mg, 78% yield). MS (ES⁺) C₂₄H₂₇F₃N₆O₄requires: 520, found: 521 [M+H]⁺.

Step 5:1-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylicacid

A mixture of tert-butyl1-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylate(134 mg, 0.257 mmol), TFA (0.992 mL, 12.9 mmol) and DCM (1 mL) wasstirred at RT for 1 h, then concentrated under reduced pressure,azeotroping with toluene, to give the title compound as a waxy residue(120 mg, 100%). MS (ES⁺) C₂₀H₁₉F₃N₆O₄ requires: 464, found: 465 [M+H]⁺.

Step 6:N-methyl-1-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

To a suspension of1-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylicacid (120 mg, 0.258 mmol), methylamine in THF (2.0 M, 0.258 mL, 0.517mmol) and BOP (149 mg, 0.336 mmol) in DMF (1.0 mL) was added DIEA (0.135mL, 0.775 mmol) and the resulting mixture was stirred at RT for 1 h thenconcentrated under reduced pressure. The residue was purified bymass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1%TFA/MeCN; Gradient: B=20-60%; 20 min; Column: C18) to give the titlecompound as an off-white solid (35 mg, 28% yield). MS (ES⁺) C₂₁H₂₂F₃N₇O₃requires: 477, found: 478 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆) δ 11.32 (s,1H), 8.55 (s, 1H), 8.47-8.41 (m, 1H), 8.19 (d, J=9.1 Hz, 1H), 7.54 (d,J=9.1 Hz, 1H), 7.47 (t, J=7.9 Hz, 1H), 7.40-7.34 (m, 2H), 7.29-7.24 (m,1H), 4.44 (t, J=7.0 Hz, 2H), 3.85 (s, 2H), 2.88 (t, J=7.6 Hz, 2H), 2.75(d, J=4.7 Hz, 3H), 1.92-1.84 (m, 2H), 1.69-1.59 (m, 2H).

Example 192:N-methyl-1-(4-(6-(2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

Steps 1-3

Step 1: 2-methyl-4-(3-(trifluoromethoxy)phenyl)pyridine

A mixture of 4-bromo-2-methylpyridine (1.2 g, 7.0 mmol),(3-(trifluoromethoxy)phenyl)boronic acid (1.87 g, 9.07 mmol) andPdCl₂(dppf)-CH₂Cl₂ (0.285 g, 0.349 mmol) in DME (23 mL) was degassed bybubbling through N₂ for 5 min. Aq. K₂CO₃ (2.0 M, 10.5 mL, 20.9 mmol) wasadded and the mixture was degassed by bubbling through N₂ for anadditional 5 min. The mixture was stirred at 70° C. for 12 h, thendiluted with EtOAc (25 mL) and water (25 mL) and the layers wereseparated. The aqueous layer was extracted with EtOAc (2×25 mL), and thecombined organic layers were concentrated under reduced pressure. Theresidue was purified by SiO₂ gel chromatography (0% to 100% EtOAc with20% MeOH in hexanes) to give the title compound as a yellow liquid (1.6g, 91% yield). MS (ES⁺) C₁₃H₁₀F₃NO requires: 253, found: 254 [M+H]⁺.

Step 2: methyl 2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetate

To a solution of 2-methyl-4-(3-(trifluoromethoxy)phenyl)pyridine (1.6 g,6.3 mmol) in THF (12.6 ml) at −78° C. was added LDA in THF (2.0 M, 9.48ml, 19.0 mmol) and the resulting mixture was stirred at −78° C. for 30min. Dimethyl carbonate (0.639 ml, 7.58 mmol) was then added and themixture was stirred at −78° C. for 1 h. The reaction was quenched withsat. aq. NH₄Cl (10 mL) at −78° C. and diluted with water (10 mL). Themixture was extracted with EtOAc (3×10 mL) and the combined organiclayers were dried over MgSO₄, filtered and concentrated under reducedpressure. The residue was purified by SiO₂ gel chromatography (0% to100% EtOAc with 20% MeOH in hexanes) to give the title compound as abrown liquid (1.8 g, 92% yield). MS (ES⁺) C₁₅H₁₂F₃NO₃ requires: 311,found: 312 [M+H]⁺.

Step 3: lithium 2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetate

To a solution of methyl2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetate (1.8 g, 5.8 mmol)in THF (23 mL) and MeOH (5.8 ml) at RT was added aq. LiOH (2.0 M, 3.1ml, 6.2 mmol) and the resulting mixture was stirred at RT for 1 h. Thereaction mixture was concentrated under reduced pressure (bath <35° C.)and lyophilized to give the title compound as a light orange solid (1.75g, 100% yield). MS (ES⁺) C₁₄H₁₀F₃NO₃ requires: 297, found: 298 [M+H]⁺.

Steps 4 to 6

Step 4:1-(4-(6-aminopyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylic acid

A mixture of tert-butyl1-(4-(6-aminopyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylate (265mg, 0.832 mmol), TFA (1.0 mL, 13 mmol) and DCM (2.1 mL) was stirred atRT for 1 h, then concentrated under reduced pressure, azeotroping withtoluene, to give the title compound as a waxy residue that wasimmediately used in the next step.

Step 5:1-(4-(6-aminopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

To a suspension of1-(4-(6-aminopyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylic acid(0.832 mmol), methylamine hydrochloride (97 mg, 1.4 mmol) and DIEA(0.499 mL, 2.86 mmol) in DMF (4.8 ml) was added HATU (471 mg, 1.24 mmol)and the resulting mixture was stirred at RT for 1 h. The reactionmixture was concentrated under reduced pressure, and the residue waspurified by SiO₂ gel chromatography (0% to 30% MeOH in DCM with 1%NH₄OH) to give the title compound as a pale yellow solid (66 mg, 29%yield). MS (ES⁺) C₁₂H₁₇N₇O requires: 275, found: 276 [M+H]⁺.

Step 6:N-methyl-1-(4-(6-(2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

To a suspension of lithium2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetate (702 mg, 2.26mmol) and1-(4-(6-aminopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide(500 mg, 1.82 mmol) in DMF (6.0 ml) at 0° C. was added T3P® in DMF (50wt. %, 462 mg, 7.26 mmol) dropwise and the resulting mixture was allowedto warm to RT over 30 min and then stirred for 2 h. The brown mixturewas adsorbed onto Celite® and purified by SiO₂ gel chromatography (0% to15% MeOH in DCM with 0.5% NH₄OH) to give a tan solid. The solid was thentriturated with EtOAc (10 mL) to give the title compound as a light tansolid (361 mg, 34%). MS (ES⁺) C₂₆H₂₅F₃N₈O₄ requires: 554, found: 555[M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆) δ 11.31 (s, 1H), 8.61 (d, J=5.1 Hz,1H), 8.55 (d, J=1.2 Hz, 1H), 8.47-8.37 (m, 1H), 8.22 (d, J=9.1 Hz, 1H),7.87 (d, J=7.9 Hz, 1H), 7.81 (d, J=10.5 Hz, 2H), 7.72-7.64 (m, 2H), 7.56(d, J=9.2 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 4.45 (t, J=7.0 Hz, 2H), 4.08(s, 2H), 2.89 (t, J=7.6 Hz, 2H), 2.76 (d, J=4.4 Hz, 3H), 1.96-1.84 (m,2H), 1.72-1.59 (m, 2H).

Example 211:1-(2-fluoro-4-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

Steps 1 to 4

Step 1: 6-iodo-N,N-bis(4-methoxybenzyl)pyridazin-3-amine

To a solution of 6-iodopyridazin-3-amine (1.00 g, 4.52 mmol) in DMF (20mL) at 0° C. was added sodium hydride (60% in mineral oil, 0.543 g, 13.6mmol) portionwise. The mixture was stirred for 20 min at RT and thencooled to 0° C. 1-(chloromethyl)-4-methoxybenzene (1.56 g, 9.95 mmol)was then added, then the mixture was stirred at RT for 30 min, quenchedwith MeOH, concentrated under reduced pressure, diluted with EtOAc, andwashed with sat. aq. NaCl. The organic layer was concentrated underreduced pressure, and the residue was purified by SiO₂ gelchromatography (0% to 100% EtOAc in hexanes) to give the title compoundas a yellow liquid (1.41 g, 68% yield). MS (ES⁺) C₂₀H₂₀IN₃O₂ requires:461, found: 462 [M+H]⁺.

Step 2: diethyl 2-(6-(bis(4-methoxybenzyl)amino)pyridazin-3-yl)malonate

A mixture of copper(I) iodide (0.178 g, 0.932 mmol), picolinic acid(0.230 g, 1.86 mmol), Cs₂CO₃ (9.11 g, 28.0 mmol),6-iodo-N,N-bis(4-methoxybenzyl)pyridazin-3-amine (4.30 g, 9.32 mmol) anddiethyl malonate (2.99 g, 18.6 mmol) in 1,4-dioxane (40 mL) wasevacuated and backfilled with nitrogen three times. The mixture washeated to 85° C. and stirred for 1 h. The mixture was then treated withSiO₂ gel (20 g), filtered, and the filtrate was concentrated underreduced pressure. The residue was purified by SiO₂ gel chromatography(0% to 75% EtOAc in hexanes) to give the title compound as a brownliquid (3.3 g, 72% yield). MS (ES⁺) C₂₇H₃₁N₃O₆ requires: 493, found: 494[M+H]⁺.

Step 3: diethyl2-(6-(bis(4-methoxybenzyl)amino)pyridazin-3-yl)-2-(3-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)-2-fluoropropyl)malonate

A mixture of K₂CO₃ (428 mg, 3.10 mmol), diethyl2-(6-(bis(4-methoxybenzyl)amino)pyridazin-3-yl)malonate (1.67 g, 3.38mmol), and tert-butyl1-(2-fluoro-3-iodopropyl)-1H-1,2,3-triazole-4-carboxylate (1.00 g, 2.82mmol) in DMF (10 mL) was stirred at RT for 16 h. The mixture was dilutedwith water and washed with EtOAc. The organic layer was concentratedunder reduced pressure and the residue was purified by SiO₂ gelchromatography (0% to 100% EtOAc in hexanes) to give the title compound(1.01 g, 50% yield). MS (ES⁺) C₃₇H₄₅FN₆O₈ requires: 720, found: 721[M+H]⁺.

Step 4:1-(4-(6-(bis(4-methoxybenzyl)amino)pyridazin-3-yl)-2-fluorobutyl)-1H-1,2,3-triazole-4-carboxylicacid

A mixture of diethyl2-(6-(bis(4-methoxybenzyl)amino)pyridazin-3-yl)-2-(3-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)-2-fluoropropyl)malonate(0.900 g, 1.25 mmol), THF (36 mL), MeOH (12 mL), and water (6 mL) wastreated with lithium hydroxide (0.150 g, 6.24 mmol) and stirred at 45°C. for 16 h. The mixture was concentrated under reduced pressure andthen 1:1 v: v MeOH/water (20 mL) was added. The pH was adjustedcarefully to 4-5 using 1 M aq. HCl, and the mixture was heated up to 90°C. and stirred for 2 h, then concentrated under reduced pressure andtreated with 15% MeOH in DCM. The mixture was shaken vigorously,filtered through a Celite®, concentrated under reduced pressure, anddried to give the title compound, which was used without furtherpurification in the following step. MS (ES⁺) C₂₇H₂₉FN₆O₄ requires: 520,found: 521 [M+H]⁺.

Steps 5 to 7

Step 5:1-(4-(6-(bis(4-methoxybenzyl)amino)pyridazin-3-yl)-2-fluorobutyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of1-(4-(6-(bis(4-methoxybenzyl)amino)pyridazin-3-yl)-2-fluorobutyl)-1H-1,2,3-triazole-4-carboxylicacid (0.36 g, 0.69 mmol) in DMF (0.2 ml) were added HATU (0.315 g, 0.828mmol), (4-(trifluoromethyl)pyridin-2-yl)methanamine (0.158 g, 0.897mmol) and DIEA (0.482 ml, 2.76 mmol) and the resulting mixture wasstirred at RT for 1 h. The reaction mixture was concentrated underreduced pressure, diluted with water and precipitate was isolated byfiltration to give the title compound as a solid, which was used in thefollowing step without further purification. MS (ES⁺) C₃₄H₃₄F₄N₈O₃requires: 678, found: 679 [M+H]⁺.

Step 6:1-(4-(6-aminopyridazin-3-yl)-2-fluorobutyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

To1-(4-(6-(bis(4-methoxybenzyl)amino)pyridazin-3-yl)-2-fluorobutyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(0.47 g, 0.69 mmol) at 0° C. was added sulfuric acid (0.736 ml, 13.8mmol). The mixture was diluted with sat. aq. NaHCO₃ and extracted withEtOAc. The organic layer was concentrated under reduced pressure to givethe title compound, which was used in the following step without furtherpurification. MS (ES⁺) C₁₈H₁₈F₄N₈O requires: 438, found: 439 [M+H]⁺.

Step 7:1-(2-fluoro-4-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of1-(4-(6-aminopyridazin-3-yl)-2-fluorobutyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(20 mg, 0.046 mmol) in DMF (0.2 ml) were added 2-(pyridin-2-yl)aceticacid hydrochloride (10 mg, 0.059 mmol), HATU (23 mg, 0.059 mmol) andDIEA (0.029 ml, 0.16 mmol). The resulting mixture was stirred at RT for20 h. The reaction mixture was partitioned between EtOAc and water, andthe organic layer was washed with sat. aq. NaCl, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The resulting brightyellow residue was purified by SiO₂ gel chromatography (3% to 5% MeOH inDCM) to give the title compound as an orange solid (12 mg, 47% yield).MS (ES⁺) C₂₅H₂₃F₄N₉O₂ requires: 557, found: 558 [M+H]⁺. ¹H NMR (MeOH-d₄)δ 8.80 (d, J=5.4 Hz, 1H), 8.76 (d, J=5.3 Hz, 1H), 8.76 (dt, J=1.8, 8.5Hz, 1H), 8.41 (s, 1H), 8.37 (d, J=9.4 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H),7.90 (m, 1H), 7.67 (s, 1H), 7.65 (d, J=9.4 Hz, 1H), 7.58 (d, J=5.4 Hz,1H), 5.01 (m, 1H), 4.78 (s, 2H), 4.77 (m, 2H), 3.14 (m, 2H), 2.18 (m,2H).

Example 259:1-(2-fluoro-4-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

Steps 1 to 6

Step 1: (R)-1-azido-3-(benzyloxy)propan-2-ol

To a solution of (R)-2-((benzyloxy)methyl)oxirane (2.42 ml, 15.9 mmol)and NH₄Cl (1.7 g, 32 mmol) in MeOH (39.5 ml) and water (5.9 ml) wasadded NaN₃ (5.2 g, 79 mmol) and the resulting mixture was stirred at RTfor 16 h. The volatiles were removed under reduced pressure and theresidue was partitioned between EtOAc (50 mL) and water (60 mL). The twolayers were separated and the aqueous layer was extracted with EtOAc(3×50 mL). The organic layers were combined, dried over MgSO₄, filtered,and concentrated under reduced pressure to give the title compound as acolorless oil (3.01 g, 91% yield). MS (ES⁺) C₁₀H₁₃N₃O₂ requires: 207,found: 208 [M+H]⁺.

Step 2: (R)-tert-butyl1-(3-(benzyloxy)-2-hydroxypropyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of (R)-1-azido-3-(benzyloxy)propan-2-ol (3.01 g, 14.5mmol), tert-butyl propiolate (2.33 ml, 17.4 mmol), DIEA (0.253 ml, 1.45mmol), and AcOH (0.083 ml, 1.4 mmol) in DCM (58.1 ml) was addedcopper(I) iodide (0.138 g, 0.726 mmol) and the resulting mixture wasstirred at RT for 16 h. Silica gel (10 g) was added to the stirringmixture and the resulting suspension was filtered and washed with DCM(20 mL) and EtOAc (20 mL). The filtrate was concentrated under reducedpressure to give the crude title compound as an orange oil, which wasused without further purification (3.95 g, 82% yield). MS (ES⁺)C₁₇H₂₃N₃O₄ requires: 333, found: 334 [M+H]⁺.

Step 3: (S)-tert-butyl1-(3-(benzyloxy)-2-fluoropropyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of (R)-tert-butyl1-(3-(benzyloxy)-2-hydroxypropyl)-1H-1,2,3-triazole-4-carboxylate (3.95g, 11.8 mmol) and pyridine (1.909 ml, 23.70 mmol) in DCM (23.7 ml) at 0°C. was added DAST (3.13 ml, 23.7 mmol). The resulting mixture wasstirred at RT for 2.5 h, then filtered through a plug of silica gel,rinsing with DCM (50 mL). The filtrate was concentrated under reducedpressure and the residue was adsorbed onto Celite® and purified by SiO₂gel chromatography (0% to 50% EtOAc in hexanes) to give the titlecompound as a tan solid (1.78 g, 45% yield). MS (ES⁺) C₁₇H₂₂FN₃O₃requires: 335, found: 336 [M+H]⁺.

Step 4: (S)-tert-butyl1-(2-fluoro-3-hydroxypropyl)-1H-1,2,3-triazole-4-carboxylate

A reaction vessel was charged with (S)-tert-butyl1-(3-(benzyloxy)-2-fluoropropyl)-1H-1,2,3-triazole-4-carboxylate (1.78g, 5.31 mmol) and EtOAc (53.1 ml) under an atmosphere of N₂. Thesolution was degassed by bubbling through N₂ for 10 min and then with N₂still flowing, palladium hydroxide on carbon (0.746 g, 1.06 mmol) wasadded. The resulting suspension was purged with H₂ for 2 min thenstirred under an atmosphere of H₂ at 1 atm for 12 h. The reactionmixture was purged with N₂, filtered through a Celite® and concentratedunder reduced pressure to give the crude title compound as a pale yellowsolid (1.32 g, 101% yield). MS (ES⁺) C₁₀H₁₆FN₃O₃ requires: 245, found:246 [M+H]⁺.

Step 5: (S)-tert-butyl1-(2-fluoro-3-(tosyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of (S)-tert-butyl1-(2-fluoro-3-hydroxypropyl)-1H-1,2,3-triazole-4-carboxylate (1.32 g,5.38 mmol) and DMAP (0.986 g, 8.07 mmol) in DCM (26.9 ml) was added4-toluenesulfonyl chloride (1.23 g, 6.46 mmol) while maintaining thetemperature at RT by a water bath, and the resulting mixture was stirredat RT for 1.5 h. The mixture was diluted with EtOAc (100 mL) and washedwith sat. aq. NH₄Cl (2×40 mL). The organic layer was dried over MgSO₄,filtered, and concentrated under reduced pressure to give crude titlecompound, which was used without further purification (1.80 g, 84%yield). MS (ES⁺) C₁₇H₂₂FN₃O₅S requires: 399, found: 400 [M+H]⁺.

Step 6: (S)-tert-butyl1-(2-fluoro-3-iodopropyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of (S)-tert-butyl1-(2-fluoro-3-(tosyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate (2.12 g,5.31 mmol) in acetone (26.5 ml) was added NaI (0.796 g, 5.31 mmol) andthe resulting mixture was stirred at 80° C. for 3 h, then at RT for 16h. Additional NaI (2 eq., 1.6 g) was added and the mixture as stirred at90° C. for 2 h. The reaction was allowed to cool to RT, diluted with50:50 v: v EtOAc/Hexanes (150 mL) and washed with water (2×50 mL) andsat. aq. NaCl (50 mL). The organic layer was dried over MgSO₄, filtered,and concentrated under reduced pressure. The residue was purified bySiO₂ gel chromatography (0% to 50% EtOAc in hexanes) to give the titlecompound as a white solid (1.71 g, 91% yield). MS (ES⁺) C₁₀H₁₅FIN₃O₂requires: 355, found: 356 [M+H]⁺.

Steps 7 to 9

Step 7: diethyl 2-(4-(trifluoromethyl)pyridin-2-yl)malonate

To a suspension of Cs₂CO₃ (90.8 g, 279 mmol) in DMSO (200 ml) were added2-fluoro-4-(trifluoromethyl)pyridine (25 g, 150 mmol) and diethylmalonate (46 ml, 300 mmol). The resulting mixture was stirred at 80° C.for 21 h. The resulting bright yellow reaction mixture was allowed tocool to RT, the solution was decanted and the solids were filtered andwashed with DCM (using a total of 300-400 mL). The combined organiclayers were washed with water (2×400 mL), dried over Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified bySiO₂ gel chromatography (0% to 10% EtOAc in hexanes) to give the titlecompound as a bright yellow liquid (32.3 g, 70% yield). MS(ES⁺)C₁₃H₁₄F₃NO₄ requires: 305, found 306 [M+H]⁺.

Step 8: methyl 2-(4-(trifluoromethyl)pyridin-2-yl)acetate

To a solution of diethyl 2-(4-(trifluoromethyl)pyridin-2-yl)malonate(11.9 g, 39.0 mmol) in MeOH (100 ml) were added sodium methoxide in MeOH(25 wt. %, 10.0 ml, 43.7 mmol) and the resulting mixture was stirred at60° C. for 4 h. The reaction mixture was concentrated under reducedpressure, and poured onto a slurry of ice. The mixture was neutralizedwith aq. HCl (1 M, 45 mL, 45 mmol), extracted with EtOAc (200 mL), andthe organic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a crude dark-yellow liquid. The residue waspurified by SiO₂ gel chromatography (10% to 20% EtOAc in hexanes) togive the title compound as a pale yellow liquid (5.66 g, 66% yield).MS(ES⁺) C₉H₈F₃NO₂ requires: 219, found 220 [M+H]⁺.

Step 9: 2-(4-(trifluoromethyl)pyridin-2-yl)acetamide

To a solution of methyl 2-(4-(trifluoromethyl)pyridin-2-yl)acetate (6.04g, 27.6 mmol) in MeOH (10 ml) was added ammonia (7 M in MeOH, 40 ml, 280mmol). The reaction mixture was stirred at RT for 21 h, thenconcentrated under reduced pressure. The residue was taken up inhexanes/EtOAc and filtered. The collected solids were dried to give acrop of product as a white powder and the remaining filtrate wasconcentrated under reduced pressure to give another crop of product as apale-yellow solid. The combined product was used without furtherpurification (5.40 g, 96% yield). MS(ES⁺) C₈H₇F₃N₂O requires: 204, found205 [M+H]⁺.

Steps 10 to 13

Step 10: (R)-di-tert-butyl2-(3-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)-2-fluoropropyl)-2-(6-iodopyridazin-3-yl)malonate

A mixture of K₂CO₃ (257 mg, 1.86 mmol), di-tert-butyl2-(6-iodopyridazin-3-yl)malonate (781 mg, 1.86 mmol), and (S)-tert-butyl1-(2-fluoro-3-iodopropyl)-1H-1,2,3-triazole-4-carboxylate (600 mg, 1.69mmol) was evacuated and backfilled with N₂, and then DMF (5.6 mL) wasadded. The mixture was evacuated and backfilled with N₂ three times,then stirred for 24 h at RT and another 24 h at 33° C. The mixture wasdiluted with 1:1 v: v EtOAc/hexanes (30 mL) and washed twice with water(30 mL then 15 mL). The combined aqueous layers were extracted with 1:1v: v EtOAc/hexanes (15 mL). The combined organic layers wereconcentrated under reduced pressure to give crude title compound as afoamy solid, which was used without further purification. MS (ES⁺)C₂₅H₃₅FIN₅O₆ requires: 647, found: 648 [M+H]⁺.

Step 11:(R)-1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylicacid

To a solution of (R)-di-tert-butyl2-(3-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)-2-fluoropropyl)-2-(6-iodopyridazin-3-yl)malonate(1.09 g, 1.69 mmol) in DCM (14.1 ml) was added TFA (14.1 ml), and themixture was stirred at 40° C. for 1 h. The mixture was concentratedunder reduced pressure to give an oily mixture, which was treated withTHF (10 mL) and then concentrated under reduced pressure to give thecrude title compound as a solid, which was used in the following stepwithout further purification. MS (ES⁺) C₁₁H₁₁HN₅O₂ requires: 391, found:392 [M+H]⁺.

Step 12:((R)-1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

A mixture of(R)-1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylicacid (661 mg, 1.69 mmol) and HATU (861 mg, 2.26 mmol) in DMF (8.4 mL)was treated with DIEA (1.475 mL, 8.468 mmol). The mixture was stirredfor 20 min and then methylamine in THF (2.0 M, 1.689 mL, 3.378 mmol) wasadded. The reaction was vigorously stirred for 40 min (precipitate formsover time), diluted with water (5 mL), and then concentrated underreduced pressure to give a solid, which was triturated in water.Precipitate was isolated by filtration, washed with water then EtOAc,and dried to give the crude title compound, which was used in thefollowing step without further purification (380 mg, 56% yield). MS(ES⁺) C₁₂H₁₄FIN₆O requires: 404, found: 405 [M+H]⁺.

Step 13:(R)-1-(2-fluoro-4-(6-(2-(4-(trifluoromethyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

A mixture of Pd(PPh₃)₄ (11.4 mg, 9.90 mol), Xantphos (11.4 mg, 0.020mmol), Cs₂CO₃ (64.5 mg, 0.198 mmol),2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (20 mg, 0.099 mmol), and(R)-1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide(40 mg, 0.099 mmol) in 1,4-dioxane (1 mL) was evacuated and back-filledwith N₂ three times. The mixture was stirred at 75° C. for 2.5 h. Thereaction mixture was directly loaded onto silica gel and purified bySiO₂ gel chromatography (0% to 25% DCM in MeOH) to give impure titlecompound as a brown solid. Further purification by reverse phasepreparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN;Gradient: B=20-50%; 12 min; Column: C18) gave the title compound as anoff-white solid (27 mg, 57% yield). MS (ES⁺) C₂₀H₂₀F₄N₈O₂ requires: 480,found: 481 [M+H]⁺. ¹H NMR (DMSO-d₆) δ 11.38 (s, 1H), 8.80 (d, J=5.2 Hz,1H), 8.51 (s, 1H), 8.46 (q, J=4.6, Hz, 1H), 8.21 (d, J=9.2 Hz, 1H), 7.81(s, 1H), 7.67 (d, J=4.6 Hz, 1H), 7.61 (d, J=9.3 Hz, 1H), 5.03 (m, 1H),4.77 (m, 2H), 4.17 (s, 2H), 3.05 (m, 2H), 2.75 (d, J=5.7 Hz, 3H), 2.08(m, 2H). The title compound (1 mg/mL, 10 μL per injection) was analyzedon a Shimadzu Prominence HPLC system with a Lux Cellulose 4 column(4.6×150 millimeter, 5 micrometer, 1 mL/min) using a mobile phase ofwater: acetonitrile (40:60), and showed an ee of >98%.

Example 272:(R)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

Step 1: 2-bromo-4-(3,3-difluorocyclobutoxy)pyridine

To a solution of 2-bromo-4-fluoropyridine (5.0 g, 28 mmol) in DMF (100ml) were added 3,3-difluorocyclobutanol (3.07 g, 28.4 mmol) and Cs₂CO₃(18.5 g, 56.8 mmol) and the resulting mixture was stirred at 60° C. for2 h. The volatiles were removed under reduced pressure. DCM was addedand the suspension was filtered. The filtrate was concentrated underreduced pressure. The residue was purified by SiO₂ gel chromatography(0% to 30% EtOAc in hexanes) to give the title compound as a pale yellowliquid (2.7 g, 36% yield). MS (ES⁺) C₉H₈ClF₂NO requires: 263, found: 264[M+H]⁺.

Step 2: tert-butyl 2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetate

A degassed solution of 2-bromo-4-(3,3-difluorocyclobutoxy)pyridine (2.7g, 10 mmol), (2-(tert-butoxy)-2-oxoethyl)zinc(II) chloride in Et₂O (0.5M, 40.9 ml, 20.4 mmol), Pd₂(dba)₃ (0.468 g, 0.511 mmol) and X-Phos(0.244 g, 0.511 mmol) in THF (30 ml) was stirred at 65° C. for 1 h. Themixture was concentrated under reduced pressure, and sat. aq. NH₄Cl (30mL) was added. The aqueous phase was extracted with EtOAc (3×20 mL), andthe combined organic layers were washed with sat. aq. NaCl, dried overMgSO₄, filtered and concentrated under reduced pressure. The residue waspurified by SiO₂ gel chromatography (0% to 60% EtOAc in hexanes) to givethe title compound as a pale yellow liquid (2.5 g, 82% yield). MS (ES⁺)C₁₅H₁₉F₂NO₃ requires: 299, found: 244 [M-(t-Bu)+2H]⁺.

Step 3: methyl 2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetate

To a solution of tert-butyl2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetate (2.5 g, 8.4 mmol) inMeOH (50 ml) were added dropwise acetyl chloride (5.9 ml, 84 mmol) andthe resulting mixture was stirred at 60° C. for 4 h then concentratedunder reduced pressure. The reaction mixture was partitioned betweenEtOAc (100 mL) and sat. aq. NaHCO₃ (100 mL). The aqueous layer wasextracted with EtOAc (3×50 mL), and the combined organic layers werewashed with sat. aq. NaCl, dried over MgSO₄, filtered and concentratedunder reduced pressure to give the title compound as a yellow liquid,which was used without further purification (2.1 g, 98% yield). MS (ES⁺)C₁₂H₁₃F₂NO₃ requires: 257, found: 258 [M+H]⁺.

Step 4: 2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetamide

A mixture of methyl 2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetate(2.1 g, 8.2 mmol) and ammonia in MeOH (7 M, 23.3 ml, 163 mmol) wasstirred at 80° C. for 16 h in a pressure vessel, allowed to cool to RT,then concentrated under reduced pressure. The residue was trituratedwith Et₂O to give the title compound as a pale yellow solid (1.9 g, 96%yield). MS (ES⁺) C₁₁H₁₂F₂N₂O₂ requires: 242, found: 243 [M+H]⁺.

Step 5: (R)-di-tert-butyl2-(3-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)-2-fluoropropyl)-2-(6-(2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)malonate

A degassed solution of2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetamide (1.12 g, 4.63mmol), (R)-di-tert-butyl2-(3-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)-2-fluoropropyl)-2-(6-iodopyridazin-3-yl)malonate(3.0 g, 4.6 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.65g, 0.93 mmol), Xantphos (1.072 g, 1.853 mmol) and Cs₂CO₃ (3.02 g, 9.27mmol) in 1,4-dioxane (30 ml) was stirred at 80° C. for 16 h. The mixturewas concentrated under reduced pressure, and the residue was purified bySiO₂ gel chromatography (0% to 4% MeOH in DCM) to give the titlecompound as a yellow solid (1.21 g, 34% yield). MS (ES⁺) C₃₆H₄₆F₃N₇O₈requires: 761, found: 762 [M+H]⁺.

Step 6:(R)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-1H-1,2,3-triazole-4-carboxylicacid

A solution of (R)-di-tert-butyl2-(3-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)-2-fluoropropyl)-2-(6-(2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)malonate(1.15 g, 1.51 mmol) in TFA (5 ml) and 1,2-dichloroethane (5 ml) wasstirred at 70° C. for 16 h. The mixture was concentrated under reducedpressure, and the residue was diluted with ACN (20 ml) and TEA (1 ml)was added. The resulting precipitate was isolated by filtration andwashed with ACN to give the title compound as a pale yellow solid (455mg, 60% yield). MS (ES⁺) C₂₂H₂₂F₃N₇O₄ requires: 505, found: 506 [M+H]⁺.

Step 7:(R)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

To a solution of(R)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-1H-1,2,3-triazole-4-carboxylicacid (410 mg, 0.811 mmol) in DMF (4 ml) were added HATU (339 mg, 0.892mmol), DIEA (0.425 ml, 2.433 mmol) and methylamine in THF (2.0 M, 0.608ml, 1.22 mmol) and the resulting mixture was stirred at 20° C. for 0.5 hthen concentrated under reduced pressure. Water was added and resultingprecipitate was isolated by filtration to give the title compound as ayellow solid (395 mg, 94% yield). MS (ES⁺) C₂₃H₂₅F₃N₈O₃ requires: 518,found: 519 [M+H]⁺. ¹H NMR (DMSO-d₆) δ 11.29 (s, 1H), 8.52 (s, 1H), 8.47(m, 1H), 8.36 (m, 1H), 8.22 (d, J=9.1 Hz, 1H), 7.60 (d, J=9.2 Hz, 1H),7.00 (m, 1H), 6.87 (m, 1H), 5.03 (m, 1H), 4.90-4.70 (m, 3H), 3.94 (s,2H), 3.28-3.22 (m, 2H), 3.08-2.98 (m, 2H), 2.79-2.70 (m, 5H), 2.20-1.95(m, 2H).

Example 255:(R)-1-(2-fluoro-4-(6-(2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

Step 1: 2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamide

A sealed tube was charged with methyl2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetate (1.0 g, 3.2 mmol)and ammonia in MeOH (7 M, 11 ml, 77 mmol). The solution was sealed andheated at 80° C. for 24 h, then allowed to cool to RT and concentratedunder reduced pressure. The residue was purified by SiO₂ gelchromatography (0% to 15% MeOH in DCM with 1% NH₄OH) to give the titlecompound as an off-white solid (0.92 g, 97% yield). MS (ES⁺)C₁₄H₁₁F₃N₂O₂ requires: 296, found: 297 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆)δ 8.57 (d, J=5.2 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.77 (s, 1H), 7.71 (d,J=1.8 Hz, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.63 (dd, J=5.3, 1.8 Hz, 1H),7.56-7.46 (m, 2H), 6.98 (s, 1H), 3.66 (s, 2H).

Step 2:(R)-1-(2-fluoro-4-(6-(2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

A vial was charged with2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamide (0.366 g, 1.24mmol),(R)-1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide(0.50 g, 1.2 mmol), Cs₂CO₃ (0.806 g, 2.47 mmol), Pd(PPh₃)₄ (0.143 g,0.124 mmol), Xantphos (0.143 g, 0.247 mmol), and 1,4-dioxane (12.4 mL).The mixture was degassed by bubbling N₂ through the suspension for 5min. The mixture was heated at 80° C. for 8 h, then allowed to cool toRT, adsorbed onto Celite® and purified by SiO₂ gel chromatography (0% to15% MeOH in DCM with 0.5% NH₄OH) to give a yellow solid (550 mg). Thesolid was triturated with 2:1 v: v EtOAc/Hexanes (2×10 mL) to give thetitle compound as an off-white solid (379 mg, 51% yield). MS (ES⁺)C₂₆H₂₄F₄N₈O₃ requires: 572, found: 573 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆)δ 11.33 (s, 1H), 8.60 (d, J=5.2 Hz, 1H), 8.52 (s, 1H), 8.46 (m, 1H),8.23 (d, J=9.2 Hz, 1H), 7.86 (dd, J=7.7, 1.5 Hz, 1H), 7.83-7.78 (m, 2H),7.70-7.66 (m, 2H), 7.61 (d, J=9.2 Hz, 1H), 7.50 (m, 1H), 5.03 (dddd,J=49.4, 11.4, 7.4, 3.3 Hz, 1H), 4.86-4.67 (m, 2H), 4.08 (s, 2H),3.09-2.96 (m, 2H), 2.76 (d, J=4.7 Hz, 3H), 2.21-1.93 (m, 2H). The titlecompound (1 mg/mL, 10 μL per injection) was analyzed on a ShimadzuProminence HPLC system with a Lux Cellulose 4 column (4.6×150millimeter, 5 micrometer, 1 mL/min) using a mobile phase of water:acetonitrile (20:80), and showed an ee of >98%.

Example 270:(R)-1-(2-fluoro-4-(6-(2-(1-(3-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

Step 1: methyl2-(1-(3-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)acetate

A mixture of 1-bromo-3-(trifluoromethoxy)benzene (2.6 g, 11 mmol),methyl 2-(1H-imidazol-4-yl)acetate (1.5 g, 11 mmol), copper(I) iodide(205 mg, 1.08 mmol), picolinic acid (133 mg, 1.08 mmol), and Cs₂CO₃(10.5 g, 32.4 mmol) in DMSO (50 ml) under Ar was stirred at 120° C. for16 h. The mixture was treated with water (100 ml), filtered, and theresidue was washed with EtOAc. The filtrate layers were separated, andthe aqueous layer was extracted with EtOAc (3×100 mL). The combinedEtOAc layers were washed with sat. aq. NaCl (100 ml), concentrated underreduced pressure and the residue purified by SiO₂ gel chromatography(25% to 75% EtOAc in petroleum ether) to give the title compound as alight brown solid (980 mg, 25%). MS (ES⁺) C₁₃H₁₁F₃N₂O₃ requires: 300,found: 301 [M+H]⁺.

Step 2: 2-(1-(3-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)acetic acid

A mixture of methyl2-(1-(3-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)acetate (980 mg, 3.27mmol) and HCl in 1,4-dioxane (4.0 M, 10 ml, 40 mmol) was stirred at 75°C. for 16 h. The mixture was concentrated under reduced pressure to givethe title compound as a light yellow solid (900 mg, 90%). MS (ES⁺)C₁₂H₉F₃N₂O₃ requires: 286, found: 287 [M+H]⁺.

Step 3: 2-(1-(3-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)acetamide

To a solution of2-(1-(3-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)acetic acid (100 mg,0.349 mmol) in DMF (1.7 ml) were added TEA (0.146 mL, 1.05 mmol) andHATU (133 mg, 0.349 mmol) and the resulting mixture was stirred at RTfor 1 h. Aq. NH₄OH (1 M, 0.110 mL, 1.1 mmol) was added and the mixturewas stirred at RT for 12 h, then concentrated under reduced pressure.The residue was purified by mass-triggered preparative HPLC (Mobilephase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 20 min;Column: C18) to give the title compound as a yellow liquid (48 mg, 34%).MS (ES⁺) C₁₂H₁₀F₃N₃O₂ requires: 285, found: 286 [M+H]⁺.

Step 4:(R)-1-(2-fluoro-4-(6-(2-(1-(3-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

A solution of(R)-1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide(50 mg, 0.12 mmol),2-(1-(3-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)acetamide2,2,2-trifluoroacetate (49 mg, 0.12 mmol), Cs₂CO₃ (141 mg, 0.433 mmol)and Xantphos (14 mg, 0.025 mmol) in 1,4-dioxane (1.24 ml) was degassedby bubbling N₂ through for 1 min, then Pd(Ph₃)₄ (14 mg, 0.012 mmol) wasadded and the mixture was further degassed for 1 min. The reactionmixture was then stirred at 70° C. for 12 h. The mixture was cooled toRT, diluted with MeOH (2 mL), filtered through Celite® and concentratedunder reduced pressure. The residue was purified by SiO₂ gelchromatography (3% to 15% MeOH in DCM) to give a pale yellow solid. Theresidue was recrystallized from hot MeOH (1 mL), and solid was isolatedby filtration, washed with MeOH (0.2 mL) and Et₂O (3×0.2 mL) and driedto give the title compound as a white solid (20 mg, 29%). MS (ES⁺)C₂₄H₂₃F₄N₉O₃ requires: 561, found: 562 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆)δ 11.16 (s, 1H), 8.52 (s, 1H), 8.47 (m, 1H), 8.34 (s, 1H), 8.25 (d,J=9.2 Hz, 1H), 7.77 (s, 1H), 7.74-7.71 (m, 2H), 7.68-7.59 (m, 2H), 7.35(d, J=8.6 Hz, 1H), 5.02 (m, 1H), 4.86-4.65 (m, 2H), 3.76 (s, 2H),3.14-2.98 (m, 2H), 2.76 (d, J=4.7 Hz, 3H), 2.14 (m, 1H), 2.00 (m, 1H).

Example 268:(R)-1-(2-fluoro-4-(6-(2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

Step 1: diethyl 2-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)malonate

To a suspension of NaH (60% in mineral oil, 1.39 g, 34.7 mmol) in DMF(116 mL) at 0° C. was added diethyl malonate (5.3 ml, 35 mmol) dropwiseand the mixture was allowed to warm to RT and stirred for 15 min.2,6-dichloro-4-(trifluoromethyl)pyridine (2.50 g, 11.6 mmol) was addedslowly and then the mixture was stirred at 70° C. for 18 h. The mixturewas allowed to cool to RT, quenched with water and the aqueous layer wasextracted with EtOAc (3×50 mL). The combined organic layers were washedwith water (3×50 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by SiO₂ gel chromatography(0% to 5% EtOAc in hexanes) to give the title compound as a colorlessliquid (2.0 g, 52%). MS (ES⁺) C₁₂H₁₁ClF₃NO₄ requires: 339, found: 340[M+H]⁺.

Step 2: diethyl 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)malonate

To a solution of diethyl2-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)malonate (2.0 g, 5.9 mmol)and ferric acetylacetonate (208 mg, 0.589 mmol) in THF (24 mL) and NMP(5.9 mL) at 0° C. was added MeMgBr in diethyl ether (3.0 M, 5.9 mL, 18mmol) dropwise and the resulting mixture was stirred at 0° C. for 5 min,then allowed to warm to RT and stirred for 30 min. Additional MeMgBr indiethyl ether (3.0 M, 29.5 mL total, 90 mmol total) was added inaliquots of 3.0 equivalents each. The mixture was cooled to 0° C. andslowly quenched with 1 M aq. HCl (100 mL), and the aqueous layer wasextracted with EtOAc (3×100 mL). The combined organic layers were washedwith water (4×50 mL) and sat. aq. NaCl (50 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by SiO₂ gel chromatography (0% to 20% EtOAc in hexanes) to givethe title compound as a yellow liquid (1.46 g, 78% yield). MS (ES⁺)C₁₄H₁₆F₃NO₄ requires: 319, found: 320 [M+H]⁺.

Step 3: methyl 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)acetate

To a solution of diethyl2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)malonate (1.46 g, 4.57 mmol)in MeOH (45.7 mL) at 0° C. was added sodium methoxide (741 mg, 13.7mmol) and the resulting mixture was stirred at RT for 12 h. The mixturewas then stirred at 45° C. for 6 h, then allowed to cool to RT andconcentrated under reduced pressure. The residue was partitioned betweenwater (20 mL) and EtOAc (40 mL) and the aqueous layer was extracted withEtOAc (3×20 mL). The combined organic layers were washed with sat. aq.K₂CO₃ (2×10 mL) and sat. aq. NaCl (10 mL), dried over Na₂SO₄, filteredand concentrated under reduced pressure to give the title compound as acolorless liquid. MS (ES⁺) C₁₀H₁₀F₃NO₂ requires: 233, found: 234 [M+H]⁺.

Step 4: 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)acetamide

A vial was charged with methyl2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)acetate (813 mg, 3.49 mmol)and ammonia in MeOH (7 M, 10.0 ml, 69.7 mmol). The vial was sealed andthe reaction mixture was stirred at RT for 72 h, then concentrated underreduced pressure to give the title compound as an off-white solid (748mg, 98%). MS (ES⁺) C₉H₉F₃N₂O requires: 218, found: 219 [M+H]⁺.

Step 5:(R)-1-(2-fluoro-4-(6-(2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

A suspension of(R)-1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide(500 mg, 1.24 mmol),2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)acetamide (297 mg, 1.36mmol) and Cs₂CO₃ (1.01 g, 3.09 mmol) in 1,4-dioxane (12.4 mL) wasdegassed by bubbling through N₂ for 1 min. Xantphos (143 mg, 0.247 mmol)and Pd(Ph₃)₄ (143 mg, 0.124 mmol) were added and the mixture wasdegassed by bubbling through N₂ for an additional 1 min. The reactionmixture was heated to 70° C. and stirred for 3 h. The mixture was cooledto RT, diluted with 1:1 v: v MeOH/DCM (4 mL), filtered through Celite®,washing with 1:1 v: v MeOH/DCM (4×3 mL) and the filtrate wasconcentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 6% MeOH in DCM) to give an off-white solid.The solid was triturated with MeOH (2 mL), collected by vacuumfiltration and washed with cold MeOH (3×0.5 mL), then taken up inmixture of ACN/water (1:1), sonicated and lyopholized to give the titlecompound as a white solid (277 mg, 44%). MS (ES⁺) C₂₁H₂₂F₄N₈O₂ requires:494, found: 495 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 11.36 (s, 1H), 8.52(s, 1H), 8.47 (m, 1H), 8.21 (d, J=9.1 Hz, 1H), 7.63-7.58 (m, 2H), 7.55(s, 1H), 5.02 (m, 1H), 4.85-4.69 (m, 2H), 4.10 (s, 2H), 3.11-2.96 (m,2H), 2.76 (d, J=4.7 Hz, 3H), 2.56 (s, 3H), 2.14 (m, 1H), 2.00 (m, 1H).

Example 251:1-(4-(6-(2-(4-cyclobutoxypyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide2,2,2-trifluoroacetate

Step 1: 2-chloro-4-cyclobutoxypyridine

To a solution of cyclobutanol (0.327 ml, 4.18 mmol) in DMF (19.01 ml) at0° C. was added sodium hydride (60% in mineral oil, 0.198 g, 4.94 mmol)and the resulting mixture was stirred at RT for 5 min.2-chloro-4-fluoropyridine (0.343 ml, 3.80 mmol) was then added dropwiseand the resulting mixture was allowed to warm to RT, then diluted withsat. aq. NaHCO₃ (5 mL) and water (10 mL) and extracted with EtOAc (3×10mL). The combined organic layers were dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified by SiO₂ gelchromatography (0% to 100% EtOAc in hexanes) to give the title compoundas a colorless liquid (570 mg, 82%). MS (ES⁺) C₉H₁₀ClNO requires: 183,found: 184 [M+H]⁺.

Step 2: tert-butyl 2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetate2,2,2-trifluoroacetate

A degassed solution of 2-chloro-4-cyclobutoxypyridine (200 mg, 1.09mmol), (2-(tert-butoxy)-2-oxoethyl)zinc(II) chloride in Et₂O (0.5 M,5.45 ml, 2.72 mmol), Pd₂(dba)₃ (100 mg, 0.109 mmol) and X-Phos (26 mg,0.054 mmol) in THF (3 ml) was stirred at 65° C. for 2 h thenconcentrated under reduced pressure. Water (10 mL) was added, themixture was extracted with EtOAc (3×5 mL), and the combined organiclayers were washed with sat. aq. NaCl, dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified bymass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1%TFA/MeCN; Gradient: B=10-50%; 12 min; Column: C18) to give the titlecompound as a white solid (187 mg, 46% yield). MS (ES⁺) C₁₅H₂₁NO₃requires: 263, found: 264 [M+H]⁺.

Step 3: 2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetamide2,2,2-trifluoroacetate

A solution of tert-butyl 2-(4-cyclobutoxypyridin-2-yl)acetate2,2,2-trifluoroacetate (185 mg, 0.490 mmol) in TFA (3 ml) and DCM (3 ml)was stirred at RT for 2 h, then concentrated under reduced pressure. Theresidue was taken up in MeOH (3 ml) and treated with thionyl chloride(0.082 ml, 1.1 mmol), and the resulting mixture was stirred at 60° C.for 1 h. The mixture was concentrated under reduced pressure, and to theresidue was added ammonia in MeOH (7 M, 3.0 ml, 21 mmol). The reactionmixture was heated in a pressure tube at 80° C. for 16 h, then allowedto cool to RT and concentrated under reduced pressure. The residue waspurified by mass-triggered preparative HPLC (Mobile phase: A=0.1%TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=0-30%; 12 min; Column: C18) togive the title compound as a colorless liquid (102 mg, 85% yield). MS(ES⁺) C₁₁H₁₄N₂O₂ requires: 206, found: 207 [M+H]⁺.

Step 4:1-(4-(6-(2-(4-cyclobutoxypyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide2,2,2-trifluoroacetate

A degassed suspension of1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide(60 mg, 0.15 mmol), 2-(4-cyclobutoxypyridin-2-yl)acetamide2,2,2-trifluoroacetate (52.3 mg, 0.163 mmol), Pd(PPh₃)₄ (17 mg, 0.015mmol), Xantphos (17 mg, 0.030 mmol) and Cs₂CO₃ (145 mg, 0.445 mmol) in1,4-dioxane (2 ml) was stirred at 90° C. for 16 h, then concentratedunder reduced pressure. The residue was purified by mass-triggeredpreparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN;Gradient: B=10-40%; 20 min; Column: C18) to give the title compound as awhite solid (34 mg, 38% yield). MS (ES⁺) C₂₃H₂₇FN₈O₃ requires: 482,found: 483 [M+H]⁺. ¹H NMR (MeOH-d₄) δ8.58 (d, J=7.0 Hz, 1H), 8.39-8.33(m, 2H), 7.65 (d, J=9.2 Hz, 1H), 7.42 (d, J=2.7 Hz, 1H), 7.36 (dd, J=7.0Hz, 2.7 Hz, 1H), 5.13-4.68 (m, 6H), 3.19-3.08 (m, 2H), 2.92 (s, 3H),2.64-2.56 (m, 2H), 2.33-1.77 (m, 6H).

Example 245:1-(4-(6-(2-(5-(3,3-difluorocyclobutoxy)pyridin-3-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

Step 1: 3-bromo-5-(3,3-difluorocyclobutoxy)pyridine2,2,2-trifluoroacetate

To a solution of 5-bromopyridin-3-ol (174 mg, 1.00 mmol) in THF (5 ml)were added diisopropyl azodicarboxylate (0.389 ml, 2.00 mmol),triphenylphosphine (525 mg, 2.00 mmol) and 3,3-difluorocyclobutanol (130mg, 1.20 mmol). The mixture was stirred at 80° C. for 2 h, thenconcentrated under reduced pressure. The residue was purified bymass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1%TFA/MeCN; Gradient: B=30-70%; 12 min; Column: C18) to give the titlecompound as a yellow liquid (105 mg, 28%). MS (ES⁺) C₉H₈BrF₂NO requires:263, found: 264 [M+H]⁺.

Step 2: tert-butyl 2-(5-(3,3-difluorocyclobutoxy)pyridin-3-yl)acetate2,2,2-trifluoroacetate

A degassed solution of 3-bromo-5-(3,3-difluorocyclobutoxy)pyridine2,2,2-trifluoroacetate (100 mg, 0.264 mmol),(2-(tert-butoxy)-2-oxoethyl)zinc(II) chloride in Et₂O (0.5 M, 2.12 ml,1.06 mmol), Pd₂(dba)₃ (12 mg, 0.013 mmol) and X-Phos (6.3 mg, 0.013mmol) in THF (2 ml) was stirred at 70° C. for 1 h, then concentratedunder reduced pressure. The residue was purified by mass-triggeredpreparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN;Gradient: B=10-40%; 20 min; Column: C18) to give title compound as awhite solid (76 mg, 69%). MS (ES⁺) C₁₅H₁₉F₂NO₃ requires: 299, found: 300[M+H]⁺.

Step 3: 2-(5-(3,3-difluorocyclobutoxy)pyridin-3-yl)acetic acid

A solution of tert-butyl2-(5-(3,3-difluorocyclobutoxy)pyridin-3-yl)acetate2,2,2-trifluoroacetate (75 mg, 0.18 mmol) in TFA (1 ml) and DCM (1 ml)was stirred at 20° C. for 2 h, then concentrated under reduced pressure.The residue was freeze dried to give the title compound as a white solid(65 mg, 100% yield). MS (ES⁺) C₁₁H₁₁F₂NO₃ requires: 243, found: 244[M+H]⁺.

Step 4:1-(4-(6-(2-(5-(3,3-difluorocyclobutoxy)pyridin-3-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide2,2,2-trifluoroacetate

To a solution of 2-(5-(3,3-difluorocyclobutoxy)pyridin-3-yl)acetic acid(17.5 mg, 0.072 mmol) in DMF (0.5 ml) were added HATU (18.7 mg, 0.049mmol), DIEA (8.6 μl, 0.049 mmol) and1-(4-(6-aminopyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide2,2,2-trifluoroacetate (20 mg, 0.049 mmol) and the resulting mixture wasstirred at 20° C. for 3 h. The volatiles were removed under reducedpressure. The residue was purified by mass-triggered preparative HPLC(Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 20min; Column: C18) to give the title compound as a white solid (11 mg,35%). MS (ES⁺) C₂₃H₂₅F₃N₈O₃ requires: 518, found: 519 [M+H]⁺. ¹H NMR(DMSO-d₆) δ 11.35 (s, 1H), 8.51 (s, 1H), 8.48 (d, J=4.7 Hz, 1H),8.22-8.18 (m, 3H), 7.61 (d, J=9.3 Hz, 1H), 7.40 (m, 1H), 5.02 (m, 1H),4.89-4.69 (m, 3H), 3.84 (s, 2H), 3.28-3.18 (m, 2H), 3.07-2.99 (m, 2H),2.78-2.68 (m, 5H), 2.20-1.93 (m, 2H).

Example 262:1-(2-Fluoro-4-(6-(2-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

Step 1: 2-chloro-4-(2,2,2-trifluoroethoxy)pyridine

To a solution of 2,2,2-trifluoroethanol (0.72 ml, 9.8 mmol) in DMF (38ml) was added NaH (60% in mineral oil, 0.39 g, 9.8 mmol) and theresulting mixture was stirred at RT for 5 min. 2-Chloro-4-fluoropyridine(0.68 ml, 7.6 mmol) was added and the reaction was stirred for 18 h.Additional NaH (60% in mineral oil, 0.39 g, 9.8 mmol) and2,2,2-trifluoroethanol (0.72 ml, 9.8 mmol) were added. After 1 h, thereaction mixture was diluted with sat. aq. NaHCO₃ (10 mL) and water (30mL) and extracted with DCM (3×20 mL). The solution was dried over MgSO₄,filtered, and concentrated under reduced pressure. The residue waspurified by SiO₂ gel chromatography (0% to 100% EtOAc with 20% MeOH inhexanes) to give the title compound as a colorless liquid (1.1 g, 72%).MS (ES⁺) C₇H₅ClF₃NO requires: 211, found: 212 [M+H]⁺.

Step 2: Ethyl 2-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)acetate

Preparation of (2-ethoxy-2-oxoethyl)zinc(II) bromide reagent: To asuspension of Zn (1.2 g, 18 mmol) in THF (4.5 ml) was addedchlorotrimethylsilane (0.11 ml, 0.89 mmol) and the resulting mixture wasstirred at RT for 15 min. Ethyl 2-bromoacetate (0.99 ml, 8.9 mmol) inTHF (13 ml) was added and the resulting mixture was stirred at 30° C.for 30 min. The light green mixture was taken up in a syringe andfiltered using a 0.45 uM syringe filter (PTFE) to provide(2-ethoxy-2-oxoethyl)zinc(II) bromide as a ˜0.5 M solution in THF.

Reaction: A solution of 2-chloro-4-(2,2,2-trifluoroethoxy)pyridine (200mg, 0.94 mmol), X-Phos (33 mg, 0.05 mmol) and Pd₂(dba)₃ (21 mg, 0.024mmol) in THF (6.3 mL) was degassed by bubbling through N₂ for 5 min.(2-Ethoxy-2-oxoethyl)zinc(II) bromide in THF (−0.5 M, 5.6 mL, 2.8 mmol)was added and the mixture was degassed by bubbling through N₂ for 10min. The mixture was stirred for 1 h, then diluted with EtOAc (5 mL) andtreated with sat. aq. NH₄Cl (5 mL). Layers were separated, the aqueousphase was extracted with EtOAc (3×5 mL), and the combined organic layerswere washed with sat. aq. NaCl, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 30% MeOH in DCM) to give the title compound asa colorless liquid (249 mg, 99%). MS (ES⁺) C₁₁H₁₂F₃NO₃ requires: 263,found: 264 [M+H]⁺.

Step 3: 2-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)acetamide

To ethyl 2-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)acetate (249 mg, 0.94mmol) was added ammonia in MeOH (7 M, 2.0 mL, 14 mmol) and the resultingmixture was stirred at 65° C. for 18 h, then allowed to cool to RT andconcentrated under reduced pressure. The residue was purified bymass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1%TFA/MeCN; Gradient: B=10-40%; 12 min; Column: C18) to give the titlecompound as a white powder (192 mg, 58%). MS (ES⁺) C₉H₉F₃N₂O₂ requires:234.0, found: 256.2 [M+Na]⁺.

Step 4:1-(2-fluoro-4-(6-(2-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

A solution of1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide(23 mg, 0.057 mmol), 2-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)acetamide2,2,2-trifluoroacetate (30 mg, 0.086 mmol), Cs₂CO₃ (75 mg, 0.23 mmol)and Xantphos (13 mg, 0.023 mmol) in 1,4-dioxane (0.57 mL) was degassedby bubbling through N₂ for 10 min. Pd(PPh₃)₄ (13 mg, 0.011 mmol) wasadded and the resulting solution was degassed by bubbling through N₂ for10 min. The mixture was stirred at 70° C. for 18 h, then allowed to coolto RT, filtered through Celite®, and concentrated under reducedpressure. The residue was purified by mass-triggered preparative HPLC(Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 20min; Column: C18) to give the title compound as an off-white solid (13.1mg, 36%). MS (ES⁺) C₂₁H₂₂F₄N₈O₃ requires: 510, found: 511 [M+H]⁺. ¹H NMR(DMSO-d₆) δ 11.45 (s, 1H), 8.66 (d, J=7.25 Hz, 1H), 8.52 (s, 1H), 8.48(q, J=3.86 Hz, 1H) 8.19 (d, J=9.65 Hz, 1H), 7.63 (d, J=9.21 Hz, 1H),7.46 (s, 1H), 7.37 (d, J=5.25 Hz, 1H), 5.07 (q, J=9.88 Hz, 2H),4.87-4.67 (m, 2H), 4.14, (2, 2H), 3.09-2.98 (m, 2H), 2.76 (d, J=4.58 Hz,3H), 2.22-2.06 (m, 1H), 2.06-1.95 (m, 1H), 1.21-1.13 (m, 1H).

Example 253:1-(2-fluoro-4-(6-(2-(4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

Step 1: 2-(4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)acetamide

A vial was charged with methyl2-(4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)acetate (100 mg, 0.425 mmol)and ammonia in MeOH (7 M, 607 μl, 4.25 mmol). The vial was sealed andheated at 60° C. for 12 h, then allowed to cool to RT and concentratedunder reduced pressure to give the title compound as a pale yellowliquid (94 mg, 100%). MS (ES⁺) C₁₂H₁₆N₂O₂ requires: 220, found: 221[M+H]⁺.

Step 2:1-(2-fluoro-4-(6-(2-(4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamidetrifluoroacetate

A solution of1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide(29 mg, 0.073 mmol),2-(4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)acetamide (16 mg, 0.073mmol), Cs₂CO₃ (83 mg, 0.25 mmol) and Xantphos (17 mg, 0.029 mmol) in1,4-dioxane (726 μl) was degassed by bubbling through N₂ for 1 min, thenPd(Ph₃)₄ (17 mg, 0.015 mmol) was added and the mixture was degassed bybubbling through N₂ for 1 min. The reaction mixture was stirred at 70°C. for 3 d. The mixture was allowed to cool to RT, filtered throughCelite® and concentrated under reduced pressure. The residue waspurified by mass-triggered preparative HPLC (Mobile phase: A=0.1%TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 20 min; Column: C18) togive the title compound as an off-white solid (5.3 mg, 12%). MS (ES⁺)C₂₄H₂₉FN₈O₃ requires: 496, found: 497 [M+H]⁺. ¹H NMR (500 MHz, MeOH-d₄)δ 8.72 (d, J=6.1 Hz, 1H), 8.36-8.30 (m, 1H), 7.94 (d, J=1.8 Hz, 1H),7.88 (dd, J=6.1, 1.9 Hz, 1H), 7.64 (d, J=9.2 Hz, 1H), 4.99 (m, 1H),4.83-4.68 (m, 2H), 4.13-4.03 (m, 2H), 3.65-3.55 (m, 2H), 3.22-3.07 (m,3H), 2.93 (s, 2H), 2.66 (s, 3H), 2.25-2.01 (m, 3H), 1.91-1.86 (m, 3H).

Example 258:N-methyl-1-(4-(6-(2-(4-(1,1,1-trifluoropropan-2-yl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

Step 1: methyl 2-(4-(3,3,3-trifluoroprop-1-en-2-yl)pyridin-2-yl)acetate

A suspension of methyl 2-(4-bromopyridin-2-yl)acetate (300 mg, 1.30mmol),4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane(347 mg, 1.57 mmol) and K₂CO₃ (541 mg, 3.91 mmol) in 1,4-dioxane (5.9mL) and water (0.6 mL) was degassed by bubbling through N₂ for 1 min.PdCl₂(dppf)-CH₂Cl₂ (53 mg, 0.065 mmol) was added and the mixture wasdegassed by bubbling through N₂ for 1 min. The mixture was stirred at90° C. for 2 h, then allowed to cool to RT, filtered through Celite® andpartitioned between water (5 mL) and EtOAc (5 mL). The aqueous layer wasextracted with EtOAc (3×5 mL) and the combined organic layers werewashed with sat. aq. NaCl (3 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 50% EtOAc in hexanes) to give the titlecompound as a pale yellow liquid (318 mg, 99%). MS (ES⁺) C₁₁H₁₀F₃NO₂requires: 245, found: 246 [M+H]⁺.

Step 2: methyl 2-(4-(1,1,1-trifluoropropan-2-yl)pyridin-2-yl)acetate

A reaction vessel was charged with methyl2-(4-(3,3,3-trifluoroprop-1-en-2-yl)pyridin-2-yl)acetate (100 mg, 0.408mmol), 10% Pd/C (43 mg, 0.041 mmol) and EtOAc (4.1 ml) under anatmosphere of N₂. The suspension was degassed by bubbling through N₂ for1 min, and purged with H₂ for 1 min. The reaction mixture was stirredunder an atmosphere of H₂ at 1 atm for 4 h. The reaction mixture waspurged with N₂, filtered through Celite® and concentrated under reducedpressure to give the title compound as a pale yellow liquid (98 mg,97%). MS (ES⁺) C₁₁H₁₂F₃NO₂ requires: 247, found: 248 [M+H]⁺.

Step 3: lithium 2-(4-(1,1,1-trifluoropropan-2-yl)pyridin-2-yl)acetate

To a solution of methyl2-(4-(1,1,1-trifluoropropan-2-yl)pyridin-2-yl)acetate (24 mg, 0.097mmol) in THF (0.69 mL), MeOH (0.14 mL) and water (0.14 mL) was addedLiOH (5.8 mg, 0.24 mmol) and the resulting mixture was stirred at RT for2 h. The mixture was filtered, washing with MeOH, and the filtrate wasconcentrated under reduced pressure and dried by lyophilization to givethe title compound as a white solid (23 mg, 100%). MS (ES⁺) C₁₀H₁₀F₃NO₂requires: 233, found: 234 [M+H]⁺.

Step 4:N-methyl-1-(4-(6-(2-(4-(1,1,1-trifluoropropan-2-yl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of1-(4-(6-aminopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide(18 mg, 0.065 mmol) and lithium2-(4-(1,1,1-trifluoropropan-2-yl)pyridin-2-yl)acetate (13 mg, 0.054mmol) in DMF (0.54 mL) at 0° C. were added TEA (0.023 mL, 0.16 mmol) andT3P® (50 wt. % in EtOAc, 0.048 mL, 0.082 mmol) and the resulting mixturewas stirred at 0° C. for 1 h. The mixture was allowed to warm to RT andconcentrated under reduced pressure. The residue was purified bymass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1%TFA/MeCN; Gradient: B=20-50%; 16 min; Column: C18) to give the titlecompound as a pale yellow solid (3.4 mg, 10%). MS (ES⁺) C₂₂H₂₅F₃N₈O₂requires: 490, found: 491 [M+H]⁺. ¹H NMR (600 MHz, MeOH-d₄) δ 8.70 (d,J=5.7 Hz, 1H), 8.43 (d, J=9.2 Hz, 1H), 8.32 (s, 1H), 7.82 (m, 1H), 7.72(m, 1H), 7.69 (d, J=9.2 Hz, 1H), 4.50 (t, J=6.9 Hz, 2H), 3.92 (m, 1H),2.99 (t, J=7.6 Hz, 2H), 2.92 (s, 3H), 2.04-1.94 (m, 2H), 1.82-1.73 (m,2H), 1.60-1.57 (m, 3H).

Example 267:(R)-1-(4-(6-(2-(4-(cyclopropyldifluoromethyl)pyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

Step 1: N-methoxy-N,2-dimethylisonicotinamide

A mixture of 2-methylisonicotinic acid (4.0 g, 29 mmol), HATU (16.5 g,1.14 mol) and DIEA (15.0 g, 116 mmol) in DMF (30 ml) was stirred at RTfor 30 min, then N,O-dimethylhydroxylamine hydrochloride (3.4 g, 35mmol) was added. The mixture was stirred at RT for 16 h, then dilutedwith water (100 ml) and extracted with 10:1 v: v DCM/MeOH (3×200 ml).The combined organic layers were washed with sat. aq. NaCl (3×200 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive the title compound as a brown oil (4.0 g, 76%) MS (ES⁺) C₉H₁₂N₂O₂requires: 180, found: 181 [M+H]⁺.

Step 2: cyclopropyl(2-methylpyridin-4-yl)methanone

To a solution of N-methoxy-N,2-dimethylisonicotinamide (3.8 g, 21 mmol)in THF (100 mL) at 0° C. was slowly added cyclopropylmagnesium bromidein THF (0.5 M, 63 mmol). The mixture was stirred at 0° C. for 2 h, thentreated with sat. aq. NH₄Cl (20 mL), and the mixture was extracted withDCM (3×300 mL). The combined organic layers were concentrated underreduced pressure, and the residue was purified by SiO₂ gelchromatography (0% to 7% MeOH in DCM) to give the title compound as ayellow oil (2.3 g, 67%). MS (ES⁺) C₁₀H₁₁NO requires: 161, found: 162[M+H]⁺.

Step 3: 4-(cyclopropyldifluoromethyl)-2-methylpyridine

A mixture of cyclopropyl(2-methylpyridin-4-yl)methanone (1.0 g, 6.2mmol) and BAST (5.5 g, 25 mmol) was stirred at 60° C. for 8 h then addedto ice water (30 mL). The resulting mixture was extracted with DCM (3×50mL), and the combined organic layers were concentrated under reducedpressure to a black oil. The oil was purified by preparative HPLC(Mobile phase: A=0.1% ammonium hydroxide/H₂O, B=acetonitrile; Gradient:B=5%-95% in 18 min; Column: C18) to give the title compound as a blackoil (150 mg, 13%). MS (ES⁺) C₁₀H₁₁F₂N requires: 183, found: 184 [M+H]⁺.

Step 4: methyl 2-(4-(cyclopropyldifluoromethyl)pyridin-2-yl)acetate

To a solution of 4-(cyclopropyldifluoromethyl)-2-methylpyridine (100 mg,0.55 mmol) in THF (10 mL) at −78° C. was slowly added LDA in THF (2.0 M,2.75 mmol). The mixture was stirred at −78° C. for 30 min. Dimethylcarbonate (59 mg, 0.66 mmol) was added. The mixture was stirred at −78°C. for 2 h. The reaction was quenched with water at −78° C., allowed towarm to RT, and extracted with EtOAc (3×50 mL). The combined organiclayers were washed with sat. aq. NaCl (100 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the crude titlecompound as a yellow oil (130 mg, 100%). MS (ES⁺) C₁₂H₁₃F₂NO₂ requires:241, found: 242 [M+H]⁺.

Step 5: 2-(4-(cyclopropyldifluoromethyl)pyridin-2-yl)acetamide

A mixture of methyl 2-(4-(cyclopropyldifluoromethyl)pyridin-2-yl)acetate(130 mg, 0.55 mmol) and ammonia in MeOH (7 M, 6 mL) was stirred at 60°C. for 16 h then concentrated under reduced pressure. The residue waspurified by preparative HPLC (Mobile phase: A=0.1% ammoniumhydroxide/H₂O, B=acetonitrile; Gradient: B=5%-95% in 18 min; Column:C18) to give the title compound as a yellow oil (33 mg, 27%). MS (ES⁺)C₁₁H₁₂F₂N₂O requires: 226, found: 227 [M+H]⁺.

Step 6:(R)-1-(4-(6-(2-(4-(cyclopropyldifluoromethyl)pyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

A mixture of Pd(PPh₃)₄ (9.3 mg, 8.0 mol), Xantphos (9.3 mg, 0.016 mmol),Cs₂CO₃ (52 mg, 0.16 mmol),2-(4-(cyclopropyldifluoromethyl)pyridin-2-yl)acetamide (20 mg, 0.088mmol), and(R)-1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide(32 mg, 0.080 mmol) in 1,4-dioxane (0.27 mL) was evacuated andback-filled with N₂ three times. The mixture was stirred at 55° C. for12 h, then concentrated under reduced pressure, and the residue waspartitioned between Et₂O (4 mL) and 1:1 v: v sat. aq. NH₄Cl/water (4mL). The mixture was vortexed and precipitate was isolated byfiltration, rinsing with Et₂O and water, and purified by mass-triggeredpreparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN;Gradient: B=20-60%; 12 min; Column: C18) to give the title compound (3.2mg, 8% yield) as a off-white solid. MS (ES⁺) C₂₃H₂₅F₃N₈O₂ requires: 502,found: 503 [M+H]⁺. ¹H NMR (DMSO-d₆) δ 11.36 (s, 1H), 8.66 (d, J=5.2 Hz,1H), 8.51 (s, 1H), 8.47 (q, J=4.6, Hz, 1H), 8.22 (d, J=9.2 Hz, 1H), 7.60(m, 2H), 7.47 (d, J=5.3 Hz, 1H), 5.03 (m, 1H), 4.76 (m, 2H), 4.09 (s,2H), 3.03 (m, 2H), 2.76 (d, J=5.7 Hz, 3H), 2.06 (m, 2H), 1.71 (m, 1H),0.72 (m, 4H).

Example 227:N-methyl-1-(4-(6-(2-(2-oxo-4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

Step 1: methyl2-(2-oxo-4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)acetate

A degassed suspension of methyl 2-(2-oxopiperazin-1-yl)acetatehydrochloride (104 mg, 0.498 mmol), 1-bromo-3-(trifluoromethoxy)benzene(120 mg, 0.498 mmol), Pd(OAc)₂ (11 mg, 0.050 mmol), Xantphos (14 mg,0.025 mmol) and Cs₂CO₃ (487 mg, 1.50 mmol) in 1,4-dioxane (3 ml) wasstirred at 100° C. for 3 h. The reaction mixture was filtered throughCelite®, and the filtrate was concentrated under reduced pressure. Theresidue was purified by mass-triggered preparative HPLC (Mobile phase:A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=30-70%; 12 min; Column:C18) to give the title compound as a colorless liquid (66 mg, 50%). MS(ES⁺) C₁₄H₁₅F₃N₂O₄ requires: 332, found: 333 [M+H]⁺.

Step 2: 2-(2-oxo-4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)aceticacid

To a solution of methyl2-(2-oxo-4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)acetate (60 mg,0.18 mmol) in THF (1 ml) and water (1 ml) was added LiOH (13 mg, 0.54mmol) and the resulting mixture was stirred at RT for 1 h thenconcentrated under reduced pressure. The residue was purified bymass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1%TFA/MeCN; Gradient: B=20-60%; 12 min; Column: C18) to give the titlecompound as a white solid (45 mg, 78%). MS (ES⁺) C₁₃H₁₃F₃N₂O₄ requires:318, found: 319 [M+H]⁺.

Step 3:N-methyl-1-(4-(6-(2-(2-oxo-4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide2,2,2-trifluoroacetate

A solution of2-(2-oxo-4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)acetic acid (16mg, 0.051 mmol),1-(4-(6-aminopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide2,2,2-trifluoroacetate (20 mg, 0.051 mmol), T3P® (50 wt. % in EtOAc, 163mg, 0.257 mmol) and pyridine (0.021 ml, 0.26 mmol) in DMF (0.5 ml) wasstirred at 80° C. for 0.5 h then concentrated under reduced pressure.The residue was purified by mass-triggered preparative HPLC (Mobilephase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=0-30%; 20 min;Column: C18) to give the title compound as a white solid (5 mg, 14%). MS(ES⁺) C₂₅H₂₈F₃N₉O₄ requires: 575, found: 576 [M+H]⁺. ¹H NMR (600 MHz,DMSO-d₆) δ 11.23 (s, 1H), 8.55 (s, 1H), 8.43 (m, 1H), 8.20 (m, 1H), 7.57(d, J=9.1 Hz, 1H), 7.34 (m, 1H), 6.98-6.95 (m, 1H), 6.89 (s, 1H), 6.74(d, J=8.1 Hz, 1H), 4.45 (t, J=6.9 Hz, 2H), 4.34 (s, 2H), 3.92 (s, 2H),3.61-3.55 (m, 4H), 2.90 (t, J=7.9 Hz, 2H), 2.76 (d, J=4.7 Hz, 3H),1.93-1.87 (m, 2H), 1.68-1.62 (m, 2H).

Example 228:N-methyl-1-(4-(6-(2-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

Step 1: ethyl 2-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)acetate

A degassed suspension of ethyl 2-(piperazin-1-yl)acetate (86 mg, 0.50mmol), 1-bromo-3-(trifluoromethoxy)benzene (120 mg, 0.499 mmol),Pd(OAc)₂ (11 mg, 0.050 mmol), Xantphos (14 mg, 0.025 mmol) and Cs₂CO₃(488 mg, 1.50 mmol) in 1,4-dioxane (3 ml) was stirred at 100° C. for 3h. The reaction mixture was filtered through Celite®, and the filtratewas concentrated under reduced pressure. The residue was purified bymass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1%TFA/MeCN; Gradient: B=30-70%; 12 min; Column: C18) to give the titlecompound as a colorless liquid (108 mg, 65%). MS (ES⁺) C₁₅H₁₉F₃N₂O₃requires: 332, found: 333 [M+H]⁺.

Step 2: 2-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)acetic acid2,2,2-trifluoroacetate

To a solution of ethyl2-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)acetate (100 mg, 0.301mmol) in THF (1 ml) and water (1 ml) were added LiOH (14.4 mg, 0.602mmol) and the resulting mixture was stirred at RT for 1 h thenconcentrated under reduced pressure. The residue was purified bymass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1%TFA/MeCN; Gradient: B=10-50%; 12 min; Column: C18) to give the titlecompound as a white solid (89 mg, 71%). MS (ES⁺) C₁₃H₁₅F₃N₂O₃ requires:304, found: 305 [M+H]⁺.

Step 3:N-methyl-1-(4-(6-(2-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide2,2,2-trifluoroacetate

To a solution of 2-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)aceticacid (21 mg, 0.051 mmol) in DMF (0.5 ml) were added HATU (21 mg, 0.057mmol),1-(4-(6-aminopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide2,2,2-trifluoroacetate (20 mg, 0.051 mmol) and DIEA (0.045 ml, 0.257mmol), and the resulting mixture was stirred at RT for 6 h thenconcentrated under reduced pressure. The residue was purified bymass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1%TFA/MeCN; Gradient: B=10-50%; 12 min; Column: C18) to give the titlecompound as a white solid (18 mg, 52%). MS (ES⁺) C₂₅H₃₀F₃N₉O₃ requires:561, found: 562 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 11.71 (s, 1H), 8.59(s, 1H), 8.42 (m, 1H), 8.21 (m, 1H), 7.64 (d, J=9.1 Hz, 1H), 7.37 (appart, J=8.3 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 6.95 (s, 1H), 6.80 (m, 1H),4.45 (t, J=7.0 Hz, 2H), 4.35-4.34 (m, br, 2H), 3.99-3.78 (m, 2H),3.69-3.62 (m, 2H), (3.34-3.21 (m, 4H), 2.91 (t, J=7.6 Hz, 2H), 2.75 (d,J=4.7 Hz, 3H), 1.93-1.87 (m, 2H), 1.68-1.62 (m, 2H).

Example 233:1-(4-(6-(2-(4-cyclobutoxypyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

Step 1: 2-chloro-4-cyclobutoxypyridine

To a suspension of NaH (60% in mineral oil, 0.395 g, 9.88 mmol) in DMF(38.0 ml) at 0° C. was added cyclobutanol (0.655 ml, 8.36 mmol) and theresulting mixture was stirred at 0° C. for 15 min.2-chloro-4-fluoropyridine (0.687 ml, 7.60 mmol) was then added at 0° C.and the mixture was allowed to warm to RT and stirred for 1 h. Thereaction mixture was diluted with EtOAc (20 mL), sat. aq. NaHCO₃ (20 mL)was added, and the layers were separated. The aqueous layer wasextracted with EtOAc (2×20 mL), and the combined organic layers werewashed with sat. aq. NaCl, dried over MgSO₄, filtered and concentratedunder reduced pressure. The residue was purified by SiO₂ gelchromatography (0% to 100% EtOAc in hexanes) to give the title compoundas a colorless liquid (1.3 g, 93% yield). MS (ES⁺) C₉H₁₀ClNO requires:183, found: 184 [M+H]⁺.

Step 2: tert-butyl 2-(4-cyclobutoxypyridin-2-yl)acetate

A vial was charged with 2-chloro-4-cyclobutoxypyridine (0.50 g, 2.7mmol), Pd₂(dba)₃ (0.125 g, 0.136 mmol), and X-Phos (0.065 g, 0.14 mmol).(2-(Tert-butoxy)-2-oxoethyl)zinc(II) chloride in Et₂O (0.5 M, 12 ml, 6.0mmol) was then added and the resulting mixture degassed by bubblingthrough N₂ for 5 min. The mixture was heated at 40° C. for 1 h, thenadsorbed onto silica gel and purified by SiO₂ gel chromatography (0% to10% MeOH in DCM with 1% NH₄OH) to give the title compound as a yellowoil (354 mg, 49%). MS (ES⁺) C₁₅H₂₁NO₃ requires: 263, found: 264 [M+H]⁺.

Step 3: 2-(4-cyclobutoxypyridin-2-yl)acetic acid hydrochloride

HCl in 1,4-dioxane (4.0 M, 0.665 mL, 2.66 mmol) was added to tert-butyl2-(4-cyclobutoxypyridin-2-yl)acetate (70 mg, 0.27 mmol) at 0° C. Theresulting yellow solution was stirred at RT for 2 h. The solution wasconcentrated under reduced pressure, azeotroping with heptanes, to givethe title compound as a light yellow solid (62 mg, 96%). MS (ES⁺)C₁₁H₁₃NO₃ requires: 207, found: 208 [M+H]⁺.

Step 4:1-(4-(6-(2-(4-cyclobutoxypyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

To a suspension of 2-(4-cyclobutoxypyridin-2-yl)acetic acidhydrochloride (62 mg, 0.25 mmol), HATU (97 mg, 0.25 mmol), and1-(4-(6-aminopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide2,2,2-trifluoroacetate (76 mg, 0.20 mmol) in DMF (0.98 mL) was added4-methylmorpholine (0.108 mL, 0.979 mmol) and the resulting mixture wasstirred at RT for 2 h. The mixture was diluted with MeOH and purified bymass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1%TFA/MeCN; Gradient: B=10-90%; 16 min; Column: C18) to give the titlecompound as a yellow solid (23 mg, 23% yield). MS (ES⁺) C₂₃H₂₈N₈O₃requires: 464, found: 465 [M+H]⁺; ¹H NMR (500 MHz, MeOH-d₄) δ 8.58 (d,J=6.9 Hz, 1H), 8.44 (d, J=9.0 Hz, 1H), 8.31 (s, 1H), 7.72 (d, J=9.2 Hz,1H), 7.42 (d, J=2.7 Hz, 1H), 7.35 (dd, J=7.0, 2.7 Hz, 1H), 5.08 (m, 1H),4.50 (t, J=6.9 Hz, 2H), 3.03-2.96 (m, 2H), 2.91 (s, 3H), 2.66-2.53 (m,3H), 2.34-2.21 (m, 3H), 2.03-1.90 (m, 3H), 1.87-1.71 (m, 3H).

Example 208:N-methyl-1-(4-(6-(2-(4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

Step 1: methyl 2-(4-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)acetate

A suspension of methyl 2-(4-chloropyridin-2-yl)acetate (300 mg, 1.62mmol),2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(407 mg, 1.94 mmol) and PdCl₂(dppf)-CH₂Cl₂ (132 mg, 0.162 mmol) in DME(3 mL) was degassed by bubbling through N₂ for 5 min. Aq. K₂CO₃ (2.0 M,2.42 ml, 4.85 mmol) was added and the mixture was degassed by bubblingthrough N₂ for an additional 5 min. The mixture was heated to 90° C. andstirred for 1 h. The mixture was diluted with EtOAc (10 mL) and water(10 mL) and the layers were separated. The aqueous layer was extractedwith EtOAc (10 mL) and the combined organic layers were concentratedunder reduced pressure. The residue was purified by SiO₂ gelchromatography (0% to 10% MeOH in DCM with 1% NH₄OH) to give the titlecompound as a brown liquid (154 mg, 41% yield). MS (ES⁺) C₁₃H₁₅NO₃requires: 233, found: 234 [M+H]⁺.

Step 2: methyl 2-(4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)acetate

A reaction vessel was charged with methyl2-(4-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)acetate (150 mg, 0.643mmol), 10% palladium on carbon (68 mg, 0.064 mmol) and EtOAc (6.4 mL)under an atmosphere of N₂. The suspension was degassed by bubblingthrough N₂ for 5 min and purged with H₂ for 5 min. The mixture wasstirred under an atmosphere of H₂ at 1 atm for 2 h. The reaction mixturewas purged with N₂, filtered through Celite®, and concentrated underreduced pressure to give the title compound as a clear liquid (148 mg,98%). MS (ES⁺) C₁₃H₁₇NO₃ requires: 235, found: 236 [M+H]⁺.

Step 3: lithium 2-(4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)acetate2,2,2-trifluoroacetate

To a solution of methyl2-(4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)acetate (140 mg, 0.595 mmol)in THF (2.4 mL) and MeOH (0.60 mL) was added aq. LiOH (2.0 M, 0.595 mL,1.19 mmol) and the resulting mixture was stirred at 50° C. for 1 h thenconcentrated under reduced pressure. The residue was purified bymass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1%TFA/MeCN; Gradient: B=0-30%; 20 min; Column: C18) to give the titlecompound as a pale yellow residue (96 mg, 48% yield). MS (ES⁺) C₁₂H₁₅NO₃requires: 221, found: 222 [M+H]⁺.

Step 4:N-methyl-1-(4-(6-(2-(4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of 2-(4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)acetic acid2,2,2-trifluoroacetate (36 mg, 0.11 mmol) and1-(4-(6-aminopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide(30 mg, 0.11 mmol) in DMF (0.22 mL) was added T3P® (50 wt. % in EtOAc,347 mg, 0.545 mmol) and the resulting mixture was stirred at RT for 2 h.The mixture was concentrated under reduced pressure, and the residue waspurified by mass-triggered preparative HPLC (Mobile phase: A=0.1%TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-60%; 12 min; Column: C18) togive the title compound as an orange solid (19 mg, 32% yield) afterneutralizing residual TFA with an Agilent StratoSpheres® PL-HCO₃ MPresin column (19 mg, 32% yield). MS (ES⁺) C₂₄H₃₀N₈O₃ requires: 478,found: 479 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 11.28 (s, 1H), 8.56 (s,1H), 8.46-8.38 (m, 2H), 8.22 (d, J=9.1 Hz, 1H), 7.55 (d, J=9.1 Hz, 1H),7.32 (s, 1H), 7.20 (dd, J=5.3 Hz, 1.6 Hz, 1H), 4.45 (t, J=7.0 Hz, 2H),3.99-3.91 (m, 4H), 3.44 (td, J=11.5 Hz, 2.6 Hz, 2H), 2.91-2.74 (m, 6H),1.94-1.84 (m, 2H), 1.73-1.62 (m, 6H).

Example 261:1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

Step 1:1-(4-(6-bromopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

To a solution of copper (II) bromide (1850 mg, 8.27 mmol) in ACN (35 ml)at 0-5° C. was added dropwise tert-butyl nitrite (0.540 ml, 4.54 mmol)over 1 min. The dark mixture was stirred at 0-5° C. for 5 min, then1-(4-(6-aminopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide(1020 mg, 3.70 mmol) was added all at once. The mixture was stirred at0-5° C. for 5 min then RT for 90 h. To the mixture was added 10 mL of a10% aq. NH₄Cl solution. The resulting mixture was partitioned betweenEtOAc (50 mL) and water (50 mL). The aqueous layer was extracted withEtOAc (50 mL). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a yellow-orangesolid. The solid was triturated in hot MeOH (5 mL), and the mixture wasthen chilled in a freezer at −RT for 15 min. Precipitate was isolated byfiltration, rinsing well with freezer-chilled MeOH and dried by suckingair through to afford the title compound as a yellow solid (76.1 mg,6%). MS (ES⁺) C₁₂H₁₅BrN₆O requires: 338/340, found: 361/363 (M+Na)⁺.

Step 2:1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide2,2,2-trifluoroacetate

A degassed solution of2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetamide2,2,2-trifluoroacetate (30 mg, 0.084 mmol),1-(4-(6-bromopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide(28 mg, 0.084 mmol), Pd(PPh₃)₄ (9.73 mg, 8.42 μmol), Xantphos (9.8 mg,0.017 mmol) and Cs₂CO₃ (82 mg, 0.25 mmol) in 1,4-dioxane (1 ml) wasstirred at 90° C. for 16 h then concentrated under reduced pressure. Theresidue was purified by mass-triggered preparative HPLC (Mobile phase:A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 20 min; Column:C18) to give the title compound as a white solid (10 mg, 19%). MS (ES⁺)C₂₃H₂₆F₂N₈O₃ requires: 500, found: 501 [M+H]⁺. ¹H NMR (600 MHz, MeOH-d₄)δ 8.66 (d, J=7.0 Hz, 1H), 8.41 (d, J=8.8 Hz, 1H), 8.31 (s, 1H), 7.69 (d,J=9.2 Hz, 1H), 7.51 (d, J=2.7 Hz, 1H), 7.45 (dd, J=6.7 Hz, 2.6 Hz, 1H),5.15-5.09 (m, 1H), 4.50 (t, J=7.0 Hz, 2H), 3.35-3.26 (m, 2H), 2.99 (t,J=7.6 Hz, 2H), 2.95-2.86 (m, 5H), 2.03-1.97 (m, 2H), 1.79-1.73 (m, 2H).

Example 188:N-methyl-1-(4-(6-(2-(5-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

Step 1: methyl 2-(5-bromopyridin-3-yl)acetate hydrochloride

To a solution of 2-(5-bromopyridin-3-yl)acetic acid (216 mg, 1.00 mmol)in MeOH (5 ml) was added thionyl chloride (0.219 ml, 3.00 mmol) and theresulting mixture was stirred at 90° C. for 2 h. The volatiles wereremoved under reduced pressure and the residue was lyophilized to givethe title compound as a white solid (266 mg, 100%). MS (ES⁺) C₈H₈BrNO₂requires: 230, found: 231 [M+H]⁺.

Step 2: methyl 2-(5-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)acetate

A degassed solution of methyl 2-(5-bromopyridin-3-yl)acetatehydrochloride (80 mg, 0.30 mmol), (3-(trifluoromethoxy)phenyl)boronicacid (74.2 mg, 0.360 mmol), PdCl₂(dppf)-CH₂Cl₂ (12 mg, 0.015 mmol) andaq. K₂CO₃ (2.0 M, 0.450 ml, 0.900 mmol) in DME (3 ml) was stirred at 90°C. for 1 h. Water (10 mL) was added, and the layers were separated. Theaqueous phase was extracted with EtOAc (3×5 mL). The combined organiclayers were washed with sat. aq. NaCl, dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 50% EtOAc in hexanes) to give the titlecompound as a colorless liquid (82 mg, 88%). MS (ES⁺) C₁₅H₁₂F₃NO₃requires: 311, found: 312 [M+H]⁺.

Step 3: 2-(5-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)acetic acid

To a solution of methyl2-(5-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)acetate (80 mg, 0.26 mmol)in THF (1 ml) and water (1 ml) were added LiOH (12.3 mg, 0.514 mmol) andthe resulting mixture was stirred at RT for 1 h then concentrated underreduced pressure. Water (3 ml) was added and the solution was acidifiedwith 10% w/v aq. citric acid to pH 3. Precipitate was isolated byfiltration to give the title compound as a white solid (58 mg, 76%). MS(ES⁺) C₁₄H₁₀F₃NO₃ requires: 297, found: 298 [M+H]⁺.

Step 4:N-methyl-1-(4-(6-(2-(5-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide2,2,2-trifluoroacetate

A solution of 2-(5-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)acetic acid(15 mg, 0.052 mmol),1-(4-(6-aminopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide2,2,2-trifluoroacetate (20 mg, 0.051 mmol), T3P® (50 wt. % in EtOAc, 165mg, 0.260 mmol) and pyridine (0.021 mL, 0.26 mmol) in DMF (0.5 ml) wasstirred at 80° C. for 0.5 h then concentrated under reduced pressure.The residue was purified by mass-triggered preparative HPLC (Mobilephase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-50%; 20 min;Column: C18) to give the title compound as a white solid (18 mg, 52%).MS (ES⁺) C₂₆H₂₅F₃N₈O₃ requires: 554, found: 555 [M+H]⁺. ¹H NMR (600 MHz,DMSO-d₆) δ 11.39 (s, 1H), 8.89 (s, 1H), 8.61 (s, 1H), 8.55 (s, 1H),8.46-8.41 (m, 1H), 8.23-8.18 (m, 2H), 7.81 (d, J=7.6 Hz, 1H), 7.77 (s,1H), 7.67 (t, J=8.1 Hz, 1H), 7.56 (d, J=9.2 Hz, 1H), 7.47 (d, J=8.2 Hz,1H), 4.45 (t, J=6.9 Hz, 2H), 3.97 (s, 2H), 2.89 (t, J=7.5 Hz, 2H), 2.76(d, J=4.8 Hz, 3H), 1.93-1.84 (m, 2H), 1.68-1.60 (m, 2H).

Example 243: cyclohexyl(6-(4-(4-(methylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)pyridazin-3-yl)carbamate

To a solution of1-(4-(6-aminopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide(30.0 mg, 0.109 mmol) and pyridine (0.013 ml, 0.16 mmol) in THF (1.0 ml)was added cyclohexyl carbonochloridate (21 mg, 0.13 mmol). The mixturewas stirred at RT for 4 h, then concentrated under reduced pressure. Theresidue was purified by mass-triggered preparative HPLC (Mobile phase:A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=20-60%; 12 min; Column:C18) to give the title compound as a yellow solid (7 mg, 16% yield). MS(ES⁺) C₁₉H₂₇N₇O₃ requires: 401, found 402 [M+H]⁺. ¹H NMR (600 MHz,DMSO-d₆) δ 10.55 (s, 1H), 8.54 (s, 1H), 8.42 (appar br s, 1H), 7.98 (d,J=9.2 Hz, 1H), 7.53 (d, J=9.2 Hz, 1H), 4.72-4.63 (m, 1H), 4.44 (t, J=7.0Hz, 2H), 2.86 (t, J=7.4 Hz, 2H), 2.75 (d, J=4.6 Hz, 3H), 1.92-1.82 (m,4H), 1.76-1.67 (m, 2H), 1.67-1.58 (m, 2H), 1.55-1.19 (m, 6H).

Example 269:(R)-1-(2-fluoro-4-(6-(2-(4-(3-(2,2,2-trifluoroethoxy)cyclobutoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

Step 1: 4-(3-(benzyloxy)cyclobutoxy)-2-chloropyridine

To a suspension of NaH (60% in mineral oil, 168 mg, 4.21 mmol) in THF (5ml) was added 3-(benzyloxy)cyclobutanol (500 mg, 2.81 mmol) and theresulting mixture was stirred at RT for 10 min.2-chloro-4-fluoropyridine (369 mg, 2.81 mmol) was added, and the mixturewas stirred at 60° C. for 2 h. The mixture was allowed to cool to RT,then diluted with EtOAc (20 mL), treated with sat. aq. NH₄Cl (20 mL),and the layers were separated. The aqueous layer was extracted withEtOAc (3×15 mL) and the combined organic layers were washed with sat.aq. NaCl, dried over MgSO₄, filtered and concentrated under reducedpressure. The residue was purified by SiO₂ gel chromatography (0% to 40%EtOAc in hexanes) to give 4-(3-(benzyloxy)cyclobutoxy)-2-chloropyridineas a colorless liquid (585 mg, 72%). MS (ES⁺) C₁₆H₁₆ClNO₂ requires: 289,found: 290 [M+H]⁺.

Step 2: 3-((2-chloropyridin-4-yl)oxy)cyclobutanol

To a solution of 4-(3-(benzyloxy)cyclobutoxy)-2-chloropyridine (585 mg,2.02 mmol) in DCM (10 ml) was added BF₃Me₂S (525 mg, 4.04 mmol), and theresulting mixture was stirred at RT for 4 h then concentrated underreduced pressure. The residue was partitioned between EtOAc (50 mL) andsat. aq. NaHCO₃ (50 mL), and the layers were separated. The aqueousphase was extracted with EtOAc (3×30 mL) and the combined organic layerswere washed with sat. aq. NaCl, dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 5% MeOH in DCM) to give the title compound asa colorless liquid (370 mg, 92%). MS (ES⁺) C₉H₁₀ClNO₂ requires: 199,found: 200 [M+H]⁺.

Step 3: 2-chloro-4-(3-(2,2,2-trifluoroethoxy)cyclobutoxy)pyridine

To a suspension of NaH (60% in mineral oil, 44.5 mg, 1.85 mmol) in THF(10 ml) was added 3-((2-chloropyridin-4-yl)oxy)cyclobutanol (370 mg,1.85 mmol). After bubbling subsided, 2,2,2-trifluoroethyltrifluoromethanesulfonate (1.29 g, 5.56 mmol) was added and theresulting mixture was stirred at 60° C. for 5 h. The reaction mixturewas diluted with EtOAc (30 mL), sat. aq. NH₄Cl (30 mL) was added, andthe layers were separated. The aqueous phase was extracted with EtOAc(3×20 mL), and the combined organic layers were washed with sat. aq.NaCl, dried over MgSO₄, filtered and concentrated under reducedpressure. The residue was purified by SiO₂ gel chromatography (0% to 30%EtOAc in hexanes) to give the title compound as a pale yellow liquid(195 mg, 37%). MS (ES⁺) C₁₁H₁₁ClF₃NO₂ requires: 281, found: 282 [M+H]⁺.

Step 4: tert-butyl2-(4-(3-(2,2,2-trifluoroethoxy)cyclobutoxy)pyridin-2-yl)acetate

A degassed mixture of2-chloro-4-(3-(2,2,2-trifluoroethoxy)cyclobutoxy)pyridine (195 mg, 0.692mmol), (2-(tert-butoxy)-2-oxoethyl)zinc(II) chloride in THF (0.5 M, 2.77mL, 1.38 mmol), Pd₂(dba)₃ (31.7 mg, 0.0350 mmol) and X-Phos (16.5 mg,0.0350 mmol) was stirred at 60° C. for 0.5 h. The mixture was dilutedwith EtOAc (20 mL). Sat. aq. NH₄Cl (20 mL) was added, and the layerswere separated. The aqueous phase was extracted with EtOAc (3×10 mL),and the combined organic layers were washed with sat. aq. NaCl, driedover MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by SiO₂ gel chromatography (0% to 40% EtOAc inhexanes) to give the title compound as a pale yellow liquid (173 mg,69%). MS (ES⁺) C₁₇H₂₂F₃NO₄ requires: 361, found: 306 [M-t(Bu)+2H]⁺.

Step 5: methyl2-(4-(3-(2,2,2-trifluoroethoxy)cyclobutoxy)pyridin-2-yl)acetate

To a solution of tert-butyl2-(4-(3-(2,2,2-trifluoroethoxy)cyclobutoxy)pyridin-2-yl)acetate (172 mg,0.476 mmol) in MeOH (5 ml) were added acetyl chloride (0.338 ml, 4.76mmol) and the resulting mixture was stirred at 60° C. for 3 h thenconcentrated under reduced pressure. The reaction mixture was taken upin EtOAc (20 mL) and washed with sat. aq. NaHCO₃ (20 mL). The organiclayer was further washed with sat. aq. NaCl (10 mL), dried over MgSO₄,filtered and concentrated under reduced pressure to give the titlecompound as a pale yellow liquid (150 mg, 99%), which was used in thenext step without further purification. MS (ES⁺) C₁₄H₁₆F₃NO₄ requires:319, found: 320 [M+H]⁺.

Step 6:2-(4-(3-(2,2,2-trifluoroethoxy)cyclobutoxy)pyridin-2-yl)acetamide

A mixture of methyl2-(4-(3-(2,2,2-trifluoroethoxy)cyclobutoxy)pyridin-2-yl)acetate (150 mg,0.470 mmol) and ammonia in MeOH (7 M, 2.01 mL, 14.1 mmol) was heated ina sealed tube at 80° C. for 16 h then concentrated under reducedpressure to give the title compound as a yellow solid (140 mg, 98%),which was used without further purification. MS (ES⁺) C₁₃H₁₅F₃N₂O₃requires: 304, found: 305 [M+H]⁺.

Step 7:(R)-1-(2-fluoro-4-(6-(2-(4-(3-(2,2,2-trifluoroethoxy)cyclobutoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide2,2,2-trifluoroacetate

A degassed solution of2-(4-(3-(2,2,2-trifluoroethoxy)cyclobutoxy)pyridin-2-yl)acetamide (22.6mg, 0.0740 mmol),(R)-1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide(30 mg, 0.074 mmol), (PPh₃)₂PdCl₂ (5.21 mg, 7.42 mol), Xantphos (8.59mg, 0.0150 mmol) and Cs₂CO₃ (48.4 mg, 0.148 mmol) in 1,4-dioxane (1 ml)was stirred at 80° C. for 16 h then concentrated under reduced pressure.The residue was purified by mass-triggered preparative HPLC (Mobilephase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 20 min;Column: C18) to give the title compound as a white solid (10 mg, 19%).MS (ES⁺) C₂₅H₂₈F₄N₈O₄ requires: 580, found: 581 [M+H]⁺. ¹H NMR (600 MHz,MeOH-d₄) δ 8.60 (d, J=7.0 Hz, 1H), 8.37-8.32 (m, 2H), 7.64 (d, J=9.2 Hz,1H), 7.44 (d, J=2.5 Hz, 1H), 7.37 (dd, J=7.0 Hz, 2.6 Hz, 1H), 5.24 (m,1H), 4.98 (m, 1H), 4.82-4.69 (m, 2H), 4.44 (m, 1H), 3.91 (q, J=8.9 Hz,2H), 3.18-3.07 (m, 2H), 2.92 (s, 3H), 2.71-2.65 (m, 2H), 2.62-2.56 (m,2H), 2.23-2.02 (m, 2H).

Example 274:1-(4-(6-(2-(4-(difluoromethoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

Step 1: 2-chloro-4-(difluoromethoxy)pyridine

To a solution of 2-chloropyridin-4-ol (1.0 g, 7.7 mmol) in DMF (8 ml)were added K₂CO₃ (4.6 g, 33 mmol) and 2-chloro-2,2-difluoroacetic acid(1.0 ml, 10 mmol) (note: exothermic!) and the resulting mixture wasstirred at RT for 1 h, then stirred at 80° C. for 2 h. An additionalamount of 2-chloro-2,2-difluoroacetic acid (2.0 ml, 20 mmol) was addedand the mixture was stirred for 16 h at 60° C. then for 30 min at 80° C.The mixture was allowed to cool, filtered, and the filtrate partitionedbetween EtOAc and water. The organic layer was washed twice with water,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by SiO₂ gel chromatography (50% to 100% EtOAc inhexanes) to give the title compound as a pale yellow solid (157 mg, 11%yield). MS (ES⁺) C₆H₄C₁F₂NO requires: 179, found: 180 [M+H]⁺.

Step 2: tert-butyl 2-(4-(difluoromethoxy)pyridin-2-yl)acetate2,2,2-trifluoroacetate

A degassed solution of 2-chloro-4-(difluoromethoxy)pyridine (300 mg,1.67 mmol), (2-(tert-butoxy)-2-oxoethyl)zinc(II) chloride in Et₂O (0.5M, 8.35 ml, 4.18 mmol), Pd₂(dba)₃ (153 mg, 0.167 mmol), and X-Phos (40mg, 0.084 mmol) in THF (3 ml) was stirred at 65° C. for 2 h. The mixturewas concentrated under reduced pressure, and water (50 mL) was added tothe residue. The mixture was extracted with EtOAc (3×25 mL) and thecombined organic layers were washed with sat. aq. NaCl, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by mass-triggered preparative HPLC (Mobile phase: A=0.1%TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=30-70%; 16 min; Column: C18) toafford the title compound as a white solid (19 mg, 3% yield). MS (ES⁺)Cl₂H₁₅F₂NO₃ requires: 259, found: 204 [M-(t-Bu)+2H]⁺.

Step 3: methyl 2-(4-(difluoromethoxy)pyridin-2-yl)acetate

To a solution of tert-butyl 2-(4-(difluoromethoxy)pyridin-2-yl)acetate(20 mg, 0.077 mmol) in MeOH (2.00 ml, 49.4 mmol) was added acetylchloride (0.055 ml, 0.77 mmol) dropwise over 5 min. The resultingmixture was stirred at 60° C. for 4 h and was then concentrated underreduced pressure to give the title compound as a yellow liquid (16 mg,96%). MS (ES⁺) C₉H₉F₂NO₃ requires: 217, found 218 [M+H]⁺.

Step 4: 2-(4-(difluoromethoxy)pyridin-2-yl)acetamide

Methyl 2-(4-(difluoromethoxy)pyridin-2-yl)acetate (16 mg, 0.074 mmol)was treated with ammonia in MeOH (7 M, 1.0 ml, 7.0 mmol), and thereaction mixture was sealed in a reaction vessel and stirred at 60° C.for 16 h. The mixture was allowed to cool, then concentrated underreduced pressure to give the title compound as a yellow solid (12 mg,81% yield). MS (ES⁺) C₈H₈F₂N₂O₂ requires: 202, found: 203 [M+H]⁺.

Step 5:1-(4-(6-(2-(4-(difluoromethoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

A suspension of1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide(24 mg, 0.059 mmol), 2-(4-(difluoromethoxy)pyridin-2-yl)acetamide (11mg, 0.054 mmol), Xantphos (6.0 mg, 0.010 mmol), Pd(PPh₃)₄ (6.0 mg,0.0052 mmol) and Cs₂CO₃ (56 mg, 0.17 mmol) in 1,4-dioxane (1.5 ml) wasdegassed by bubbling through N₂ for 5 min. The reaction mixture washeated to 80° C. and stirred for 5 h, then stirred at RT for 16 h. Themixture was concentrated under reduced pressure, dissolved in DMSO,filtered and the filtrate directly purified by mass-triggeredpreparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN;Gradient: B=10-40%; 20 min; Column: C18) to give the title compound as ayellow solid. MS (ES⁺) C₂₀H₂₁F₃N₈O₃ requires: 478, found: 479 [M+H]⁺.

¹H NMR (600 MHz, DMSO-d₆) δ 11.35 (s, 1H), 8.55 (d, J=5.8 Hz, 1H), 8.52(s, 1H), 8.47 (m, 1H), 8.22 (d, J=9.2 Hz, 1H), 7.62 (d, J=9.0 Hz, 1H),7.50 (t, J=73 Hz, 1H), 7.31 (s, 1H), 7.19 (d, J=4.5 Hz, 1H), 5.03 (m,1H), 4.86-4.69 (m, 2H), 4.05 (s, 2H), 3.13-2.98 (m, 2H), 2.76 (d, J=4.7Hz, 3H), 2.21-1.96 (m, 2H).

Example 275:(R)-1-(4-(6-(2-(4-cyclopropylpyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

Step 1: methyl 2-(4-cyclopropylpyridin-2-yl)acetate

A degassed solution of methyl 2-(4-bromopyridin-2-yl)acetate (500 mg,2.17 mmol), cyclopropylzinc(II) bromide in THF (0.5 M, 2.17 mL, 10.9mmol) and PdCl₂(dppf)-CH₂Cl₂ (89 mg, 0.11 mmol) was stirred at 65° C.for 3 h. The mixture was diluted with EtOAc and washed with sat. aq.NH₄Cl. The organic layer was separated, dried over MgSO₄, andconcentrated under reduced pressure to give the crude title compound,which was used without further purification. MS (ES⁺) C₁₁H₁₃NO₂requires: 191, found: 192 [M+H]⁺.

Step 2: 2-(4-cyclopropylpyridin-2-yl)acetamide

To a solution of methyl 2-(4-cyclopropylpyridin-2-yl)acetate (415 mg,2.17 mmol) in MeOH (10 ml) was added ammonia in MeOH (7 M, 12.4 ml, 86.8mmol) and the reaction mixture was stirred at RT for 2 d. The reactionmixture was concentrated under reduced pressure, and the residue waspurified by SiO₂ gel chromatography (0% to 20% MeOH in DCM) to give thetitle compound as a tan liquid (250 mg, 65% yield). MS (ES⁺) C₁₀H₂N₂Orequires: 176, found: 177 [M+H]⁺.

Step 3:(R)-1-(4-(6-(2-(4-cyclopropylpyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide2,2,2-trifluoroacetate

A vial was charged with 2-(4-cyclopropylpyridin-2-yl)acetamide (21.8 mg,0.124 mmol),(R)-1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide(50 mg, 0.12 mmol), Cs₂CO₃ (81.0 mg, 0.247 mmol), Pd(PPh₃)₄ (11.7 mg,0.0120 mmol), Xantphos (14.3 mg, 0.0250 mmol), and 1,4-dioxane (1.24mL). The mixture was evacuated and back-filled with N₂ three times thenstirred at 60° C. for 16 h. The mixture was diluted with sat. aq. NH₄Cland extracted with DCM. The organic layer was concentrated under reducedpressure and the residue purified by mass-triggered preparative HPLC(Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-30%; 12min; Column: C18) to give the title compound as an off-white solid (9.0mg, 16% yield). MS (ES⁺) C₂₂H₂₅FN₈O₂ requires: 452, found: 453 [M+H]⁺.¹H NMR (DMSO-d₆) δ 11.48 (s, 1H), 8.58 (d, J=5.2 Hz, 1H), 8.52 (s, 1H),8.48 (q, J=4.6, Hz, 1H), 8.18 (d, J=9.2 Hz, 1H), 7.63 (d, J=9.2 Hz, 1H),7.56 (s, 1H), 7.47 (s, 1H), 5.03 (m, 1H), 4.78 (m, 2H), 4.16 (s, 2H),3.04 (m, 2H), 2.77 (d, J=5.7 Hz, 3H), 2.09 (m, 3H), 1.28 (m, 2H), 1.09(m, 2H).

Example 605:N-methyl-1-(4-(6-(2-(4-(2-(trifluoromethyl)phenyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

Step 1:1-(4-(6-(2-(4-bromopyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

To a solution of1-(4-(6-aminopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide(2.0 g, 7.2 mmol) and 2-(4-bromopyridin-2-yl)acetic acid (1.6 g, 7.2mmol) in DMF (5 ml) were added T3P® (50 wt. % in EtOAc, 9.2 g, 14 mmol)and DIEA (2.7 g, 22 mmol). The mixture was stirred at RT for 3 h, thenwater (50 mL) was added, the mixture was stirred for 30 min, andprecipitate was isolated by filtration to give the title compound as ayellow solid (1 g, 40%). MS (ES⁺) C₁₉H₂₁BrN₈O₂ requires: 473, found: 474[M+H]⁺.

Step 2:N-methyl-1-(4-(6-(2-(4-(2-(trifluoromethyl)phenyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of1-(4-(6-(2-(4-bromopyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide(60 mg, 0.12 mmol), 2-(trifluoromethyl)phenylboronic acid (60 mg, 0.25mmol), and Pd(PPh₃)₄ (15 mg, 0.012 mmol) in 1,4-dioxane (2 ml) and water(0.2 ml) was added Cs₂CO₃ (12.2 mg, 0.375 mmol), and the mixture wasstirred at 100° C. for 16 h. The mixture was concentrated under reducedpressure, DMF (3 mL) was added, the mixture was filtered, and thefiltrate was purified by preparatory HPLC (Mobile phase: A=0.1% ammoniumhydroxide/H₂O, B=acetonitrile; Gradient: B=5%-95% in 18 min; Column:C18) to afford the title compound as a white solid (28 mg, 42%). MS(ES⁺) C₂₆H₂₅F₃N₈O₂ requires: 538, found: 539 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 1.63 (m, 2H), 1.88 (m, 2H), 2.75 (d, J=6 Hz, 3H), 2.89 (t,J=9.5 Hz, 3H), 4.14 (s, 2H), 4.45 (t, J=8.5 Hz, 2H), 7.46 (appar m, 2H),7.55 (s, 1H), 7.60 (d, J=9.2 Hz, 1H), 7.76 (m, 2H), 7.91 (d, J=7.6 Hz,1H), 8.23 (d, J=9.2 Hz, 1H), 8.45 (m, 1H), 8.56 (s, 1H), 8.68 (d, J=6.5Hz, 1H), 11.42 (s, 1H).

Example 229:N-methyl-5-(4-(6-(2-(4-(trifluoromethyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-1,3,4-thiadiazole-2-carboxamide

Steps 1 to 5

Step 1: pent-4-ynehydrazide

A mixture of methyl pent-4-ynoate (100 g, 510 mmol) and hydrazinehydrate (100 mL, 1530 mmol) in EtOH (800 mL) was stirred at reflux underAr for 16 h. The mixture was concentrated under reduced pressure,azeotroping with toluene (2×250 mL), to give the title compound as awhite solid (61 g, 100%), which was used in the next step withoutfurther purification. MS (ES⁺) C₅H₈N₂O requires: 112, found: 113[M+H]⁺.

Step 2: ethyl 2-oxo-2-(2-pent-4-ynoylhydrazinyl)acetate

To a mixture of pent-4-ynehydrazide (25.0 g, 223 mmol) and TEA (62.1 mL,446 mmol) in DCM (500 mL) at 0° C. was added ethyl 2-chloro-2-oxoacetate(27.4 mL, 246 mmol). The mixture was stirred at RT for 30 min thenfiltered, washing with DCM (2×20 mL). The combined filtrates wereconcentrated under reduced pressure to give the title compound as abrown oil (60 g, >100%), which was used without further purification. MS(ES⁺) C₉H₁₂N₂O₄ requires: 212, found: 213[M+H]⁺.

Step 3: ethyl 5-(but-3-ynyl)-1,3,4-thiadiazole-2-carboxylate

A mixture of ethyl 2-oxo-2-(2-pent-4-ynoylhydrazinyl)acetate (17.5 g,8.20 mmol) in toluene (350 mL) was stirred at 60° C. for 15 min, thenP₂S₅ (20 g, 9.0 mmol) was added in portions. The mixture was stirred at60° C. for 15 min, then allowed to cool to RT. The toluene layer wasseparated, and the remaining residue was taken up in sat. aq. NaHCO₃ (25mL) and extracted with EtOAc (3×180 mL). The combined organic layerswere concentrated under reduced pressure, and the residue was purifiedby SiO₂ gel chromatography (18% to 30% EtOAc in petroleum ether) toafford the title compound as a yellow solid (3.9 g, 22%). MS (ES⁺)C₉H₁₀N₂O₂S requires: 210, found: 211 [M+H]⁺.

Step 4: ethyl5-(4-(6-aminopyridazin-3-yl)but-3-ynyl)-1,3,4-thiadiazole-2-carboxylate

A mixture of ethyl 5-(but-3-ynyl)-1,3,4-thiadiazole-2-carboxylate (13.6g, 64.8 mmol), 6-iodopyridazin-3-amine (15.0 g, 68.0 mmol), Pd(PPh₃)₂C₂(4.55 g, 6.50 mmol), copper (I) iodide (2.47 g, 1.30 mmol) and TEA (27.0mL, 194 mmol) in THF (200 mL) under Ar was stirred at 50° C. for 1 h,then filtered through a short SiO₂ gel column, washing with THF (500 mL)and 4:1 v: v DCM/EtOH (800 mL). The filtrate was concentrated underreduced pressure to afford 44 g of a brown oil, which was washed withEt₂O (200 mL×2) and 8:1 v: v Et₂O/EtOAc (200 mL). The resulting brownoil was triturated with 95% EtOH (20 mL) and water (160 mL), solid wasremoved by filtration, and the filtrate was extracted with DCM (150mL×3). The combined final organic layers were concentrated under reducedpressure to afford the title compound as a brown oil (18.9 g, 96%). MS(ES⁺) C₁₃H₁₃N₅O₂S requires: 303, found: 304 [M+H]⁺.

Step 5: ethyl5-(4-(6-aminopyridazin-3-yl)butyl)-1,3,4-thiadiazole-2-carboxylate

A reaction vessel containing ethyl5-(4-(6-aminopyridazin-3-yl)but-3-ynyl)-1,3,4-thiadiazole-2-carboxylate(18.9 g, 62.4 mmol) and Raney Ni (9.0 g) in EtOH (800 mL) was chargedwith H₂ three times, stirred at 40° C. for 1.5 h, purged with N₂,filtered, washed with hot EtOH (400 mL, 70-80° C.), and concentratedunder reduced pressure to afford 16 g of a brown oil. To this oil wasadded 40 mL of EtOAc, the mixture was stirred for 10 min, then Et₂O (200mL) was added slowly. The mixture was stirred at RT for 30 min, andsolid was isolated by filtration, washed with 1:5 v: v EtOAc/Et₂O(2×20), and dried to afford the title compound as a white solid (11.6 g,61%). MS (ES⁺) C₁₃H₁₇N₅O₂S requires: 307, found: 308[M+H]⁺.

Steps 6 to 9

Step 6: diethyl 2-(4-(trifluoromethyl)pyridin-2-yl)malonate

To a solution of 2-fluoro-4-(trifluoromethyl)pyridine (25 g, 0.15 mol)in DMSO (200 mL) were added Cs₂CO₃ (97.5 g, 0.300 mol) and diethylmalonate (48 g, 0.30 mol), and the mixture was stirred under N₂ at 80°C. for 3 h. The mixture was allowed to cool to RT, filtered, and thefiltrate was treated with DCM (200 mL). Crude title compoundcrystallized from the solution as a white solid, which was used withoutfurther purification (40 g, 87%). MS (ES⁺) C₁₃H₁₄F₃NO₄ requires: 305,found: 306 [M+H]⁺.

Step 7: ethyl 2-(4-(trifluoromethyl)pyridin-2-yl)acetate

To a solution of diethyl 2-(4-(trifluoromethyl)pyridin-2-yl)malonate(4.7 g, 0.015 mol) in DMSO (30 mL) was added lithium chloride (1.9 g,0.046 mol) and the solution was stirred under N₂ at 130° C. for 3 h,then allowed to cool to RT and treated with water (20 mL). The mixturewas extracted with EtOAc (2×50 mL), and the combined organic layers werewashed with sat. aq. NaCl, dried over Na₂SO₄, and concentrated underreduced pressure. The residue was purified by SiO₂ gel chromatography(9% EtOAc in petroleum ether) to give the title compound as a yellow oil(1.7 g, 49%). MS (ES⁺) C₁₀H₁₀F₃NO₂ requires: 233, found: 234 [M+H]⁺.

Step 8: ethyl lithium 2-(4-(trifluoromethyl)pyridin-2-yl)acetate

Lithium hydroxide (0.610 g, 14.4 mmol) was dissolved in ethanol (20 mL),then 2-(4-(trifluoromethyl)pyridin-2-yl)acetate (1.7 g, 7.2 mmol) wasadded slowly, and the reaction mixture was stirred at RT for 3 h. Themixture was concentrated under reduced pressure to give the crude titlecompound as a yellow solid, which was used without further purification(1.3 g, 86%). MS (ES⁺) C₈H₆F₃NO₂ requires: 205, found: 206 [M+H]⁺.

Step 9:N-methyl-5-(4-(6-(2-(4-(trifluoromethyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-1,3,4-thiadiazole-2-carboxamide2,2,2-trifluoroacetate

To a solution of crude lithium2-(4-(trifluoromethyl)pyridin-2-yl)acetate (21.7 mg, 0.103 mmol) in DMF(0.5 ml) were added5-(4-(6-aminopyridazin-3-yl)butyl)-N-methyl-1,3,4-thiadiazole-2-carboxamide(30 mg, 0.10 mmol), HATU (42.9 mg, 0.113 mmol) and DIEA (0.054 ml, 0.31mmol), and the resulting mixture was stirred at RT for 2 h. The mixturewas concentrated under reduced pressure, and the residue was purified bymass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1%TFA/MeCN; Gradient: B=10-50%; 12 min; Column: C18) to give the titlecompound as a white solid (3 mg, 5%). MS (ES⁺) C₂₀H₂₀F₃N₇O₂S requires:479, found: 480 [M+H]⁺. ¹H NMR (600 MHz, MeOH-d₄) δ 8.77 (d, J=5.2 Hz,1H), 8.54 (d, J=9.2 Hz, 1H), 7.82 (d, J=9.3 Hz, 1H), 7.79 (s, 1H), 7.63(d, J=5.3 Hz, 1H), 4.85 (s, 2H), 3.23 (t, J=6.8 Hz, 2H), 3.2 (t, J=7.4Hz, 2H), 2.94 (s, 3H), 1.95-1.85 (m, 4H).

Example 508:5-(3-fluoro-4-(4-(methylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1,3,4-thiadiazole-2-carboxamide

Step 1: pent-4-enehydrazide

Hydrazine hydrate (7.60 g, 152 mmol) was added to a solution of ethylpent-4-enoate (19.5 g, 152 mmol) in 120 mL of MeOH. The mixture wasstirred at RT for 48 h. The mixture was concentrated under reducedpressure to give the title compound as a white solid (11 g, 64%). MS(ES⁺) C₅H₁₀N₂O requires: 114, found: 115[M+H]⁺.

Step 2: ethyl 5-(but-3-enyl)-1,3,4-thiadiazole-2-carboxylate

To a mixture of pent-4-enehydrazide (1.14 g, 10.0 mmol) and TEA (2.1 mL,15 mmol) in anhydrous THF (20 mL) at 0° C. was slowly added ethyl oxalylchloride (1.34 mL, 12.0 mmol). The mixture was stirred at 0° C. for 30min. The mixture was concentrated under reduced pressure and the residuedissolved in toluene (20 mL). P₂S₅ (4.44 g, 20.0 mmol) was added, andthe mixture was stirred at 60° C. for 20 min. The mixture was filteredand the residue was washed with EtOAc. The filtrate was concentratedunder reduced pressure and purified by SiO₂ gel chromatography (20%EtOAc in petroleum ether) to give the title compound as a yellow oil(1.6 g, 76%). MS (ES⁺) C₉H₁₂N₂O₂S requires: 212, found: 213[M+H]⁺.

Step 3: ethyl 5-(4-azido-3-hydroxybutyl)-1,3,4-thiadiazole-2-carboxylate

To a mixture of ethyl 5-(but-3-enyl)-1,3,4-thiadiazole-2-carboxylate(10.0 g, 47.2 mmol) and NaHCO₃ (40.0 g, 476 mmol) in 10:1 v: v DCM/water(220 mL) was added m-chloroperbenzoic acid (10.0 g, 56.6 mmol). Themixture was stirred at RT for 40 min then additional m-chloroperbenzoicacid (6.00 g, 37.8 mmol) was added. The mixture was stirred at RT for 2h then additional m-chloroperbenzoic acid (8.00 g, 47.2 mmol) was added.The mixture was stirred for 2 h, then quenched with water andpartitioned between DCM and water. The aqueous layer was extracted withDCM (3×100 mL). The combined organic layers were washed with sat. aq.Na₂SO₃ and sat. aq. NaHCO₃, dried and concentrated under reducedpressure to afford a crude product, which was dissolved in 80 mL of DMF.To the solution was slowly added NaN₃ (9.20 g, 142 mmol). The mixturewas stirred at 65° C. for 16 h, then diluted with water and extractedwith EtOAc (3×150 mL). The combined organic layers were washed with sat.aq. NaCl, dried and concentrated under reduced pressure. The residue waspurified by SiO₂ gel chromatography (25% to 50% EtOAc in petroleumether) to give the title compound as a brown oil (10 g, 26%). MS (ES⁺)C₉H₁₃N₅O₃S requires: 271, found: 272[M+H]⁺.

Step 4: ethyl5-(4-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)-3-hydroxybutyl)-1,3,4-thiadiazole-2-carboxylate

A mixture of ethyl5-(4-azido-3-hydroxybutyl)-1,3,4-thiadiazole-2-carboxylate (1.0 g, 3.7mmol), tert-butyl propiolate (558 mg, 4.40 mmol), CuSO₄ (200 mg) andsodium ascorbate (400 mg) in 1:1 v: v t-BuOH/water (20 mL) was stirredat RT for 2 h. The mixture was diluted with water, then extracted withEtOAc (3×30 mL). The combined organic layers were dried and concentratedunder reduced pressure to give the title compound as a yellow solid (1.4g, 96%). MS (ES⁺) C₁₆H₂₃N₅O₅S requires: 397, found: 420[M+Na]⁺.

Step 5: ethyl5-(4-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)-3-fluorobutyl)-1,3,4-thiadiazole-2-carboxylate

To a mixture of ethyl5-(4-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)-3-hydroxybutyl)-1,3,4-thiadiazole-2-carboxylate(1.4 g, 3.5 mmol) and pyridine (0.150 mL, 1.86 mmol) in DCM (30 mL) at0° C. was slowly added DAST (2.27 g, 14.1 mmol). The mixture was stirredat 0° C. for 30 min. The mixture was added slowly to an ice-coldsaturated NaHCO₃ solution, then extracted with DCM (3×30 mL). Thecombined organic layers were dried and concentrated under reducedpressure. The residue was purified by SiO₂ gel chromatography (25% EtOAcin petroleum ether) to give the title compound as an orange solid (440mg, 31%). MS (ES⁺) C₁₆H₂₂FN₅O₄S requires: 399, found: 422[M+Na]⁺.

The next steps outline the preparation of racemic EXAMPLE 508. For thepreparation of enantiomeric enriched EXAMPLE 220 and EXAMPLE 221, achiral separation was performed at this stage and the products carriedthrough using the same general procedure. Ethyl5-(4-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)-3-fluorobutyl)-1,3,4-thiadiazole-2-carboxylatewas separated into its separate enantiomers using chiral SFC separation(column: IC 4.6*150 mm 5 um; solvent: MeOH). Enantiomers are arbitrarilyassigned in the final products.

Step 6: tert-butyl1-(2-fluoro-4-(5-((4-(trifluoromethyl)pyridin-2-yl)methylcarbamoyl)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of ethyl5-(4-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)-3-fluorobutyl)-1,3,4-thiadiazole-2-carboxylate(150 mg, 0.38 mmol) and (4-(trifluoromethyl)pyridin-2-yl)methanamine(100 mg, 0.56 mmol) in MeOH (2 mL) was stirred at 80° C. for 3 d in asealed tube. The mixture was concentrated under reduced pressure toafford the title compound as a yellow solid (195 mg, 98%). MS (ES⁺)C₂₁H₂₃F₄N₇O₃S requires: 529, found: 530[M+H]⁺.

Step 7:1-(2-fluoro-4-(5-((4-(trifluoromethyl)pyridin-2-yl)methylcarbamoyl)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylicacid

TFA (2 mL) was added to a solution of tert-butyl1-(2-fluoro-4-(5-((4-(trifluoromethyl)pyridin-2-yl)methylcarbamoyl)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylate(195 mg, 0.370 mmol) in DCM (3 mL). The mixture was stirred at RT for 3h then concentrated under reduced pressure. MeOH was added to theresidue, and precipitate was isolated by filtration to give the titlecompound as a beige solid (170 mg, 98%). MS (ES⁺) C₁₇H₁₅F₄N₇O₃Srequires: 473, found: 474[M+H]⁺.

Step 8:5-(3-fluoro-4-(4-(methylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1,3,4-thiadiazole-2-carboxamide

A mixture of1-(2-fluoro-4-(5-((4-(trifluoromethyl)pyridin-2-yl)methylcarbamoyl)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylicacid (40 mg, 0.085 mmol), methylamine hydrochloride (9.0 mg, 0.13 mmol),HATU (48 mg, 0.13 mmol) and DIEA (33 mg, 0.25 mmol) in DMF (1 mL) wasstirred at RT for 2 h then treated with water. Precipitate was isolatedby filtration and washed with MeOH to give the title compound as a whitesolid (20 mg, 49%). MS (ES⁺) C₁₈H₁₈F₄N₈O₂S requires: 486, found:487[M+H]⁺; 1H NMR (500 MHz, DMSO-d₆) δ 9.81 (t, J=6.1 Hz, 1H), 8.81 (m,1H), 8.53 (s, 1H), 8.50 (m, 1H), 7.73 (s, 1H), 7.69 (m, 1H), 5.06 (m,1H), 4.88-4.73 (m, 2H), 4.70 (d, J=6.1 Hz, 2H), 3.34 (appar s, 2H), 2.76(d, J=4.7 Hz, 3H), 2.36-2.07 (m, 2H).

Example 540:1-(2-fluoro-4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

Step 1: 1,4-dibromo-2-fluorobutane

To a solution of 1,4-dibromobutan-2-ol (50.0 g, 216 mmol) in DCM (200ml) at 0-5° C. was added DAST (38.2 g, 237 mmol). The mixture wasallowed to warm to RT and stirred for 16 h. The mixture was added to asolution of sat. aq. NaHCO₃ (200 ml) at 0-5° C. and extracted with DCM(2×200 ml). The combined organic layers were washed with sat. aq. NaCl(300 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give the presumed title compound as a yellow oil (40.0 g,80%).

Step 2: 5-bromo-4-fluoropentanenitrile

A solution of 1,4-dibromo-2-fluorobutane (5.0 g, 21 mmol) and NaCN (1.05g, 21.0 mmol) in DMF (10 mL) was stirred at RT for 16 h. Water (50 ml)was added, and the mixture was extracted with EtOAc (3×60 mL). Thecombined organic layers were washed with sat. aq. NaCl (100 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to givethe crude title compound as a yellow oil (3.78 g, 100%).

Step 3: 5-azido-4-fluoropentanenitrile

A solution of 5-bromo-4-fluoropentanenitrile (540 mg, 3.00 mmol) andsodium azide (195 mg, 3.00 mmol) in DMF (5 mL) was stirred at 70° C. for16 h to give the title compound as a solution, which was used in thenext step without purification (assumed 426 mg, 100% crude).

Step 4: ethyl 1-(4-cyano-2-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate

A solution of crude 5-azido-4-fluoropentanenitrile (426 mg, 3.00 mmol),ethyl propiolate (441 mg, 4.50 mmol) L-(+)-ascorbic acid (192 mg, 0.970mmol) and CuSO₄.5H₂O (86 mg, 0.34 mmol) in 1:1 v: v t-BuOH/water (20 ml)was stirred at RT for 3 h, then extracted with EtOAc (3×60 mL). Thecombined organic layers were washed with sat. aq. NaCl (100 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to givethe title compound as a yellow oil (450 mg, 62%). MS (ES⁺) C₁₀H₁₃FN₄O₂requires: 240, found: 241 [M+H]⁺.

Step 5: ethyl 1-(4-cyano-2-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate

A solution of ethyl1-(4-cyano-2-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate (450 mg, 1.88mmol) and hydrazinecarbothioamide (341 mg, 3.75 mmol) in TFA (5 mL) wasstirred at 70° C. for 16 h. The mixture was concentrated under reducedpressure, and to the residue was added sat. aq. NaHCO₃ (20 mL). Themixture was extracted with EtOAc (3×50 mL). The combined organic layerswere concentrated under reduced pressure to give a yellow solid, whichwas washed with water (20 mL) and Et₂O (30 mL) to give the titlecompound as a white solid (200 mg, 33%). MS (ES⁺) C₁₁H₁₅FN₆O₂S requires:314, found: 315 [M+H]⁺.

Step 6: ethyl1-(2-fluoro-4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

A solution of ethyl1-(4-(5-amino-1,3,4-thiadiazol-2-yl)-2-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate(160 mg, 0.50 mmol), 2-(pyridin-2-yl)acetic acid hydrochloride (87 mg,0.50 mmol), HATU (285 mg, 0.75 mmol) and K₂CO₃ (207 mg, 1.50 mmol) inDMF (5 mL) was stirred at RT for 16 h. The mixture was diluted withwater (30 mL), then extracted with 10:1 v: v DCM/MeOH (3×50 mL). Thecombined organic layers were washed with sat. aq. NaCl (100 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to givethe title compound as a white solid (194 mg, 89%). MS (ES⁺) C₁₈H₂₀FN₇O₃Srequires: 433, found: 434 [M+H]⁺.

Step 7:1-(2-fluoro-4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylicacid

A solution of ethyl1-(2-fluoro-4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylate(150 mg, 0.35 mmol) and LiOH (17 mg, 0.70 mmol) in 1:1 v: v THF/H₂O (5mL) was stirred at RT for 16 h. The solvent was removed, and the residuewas purified by preparative HPLC (Mobile phase: A=0.1% ammoniumhydroxide/H₂O, B=acetonitrile; Gradient: B=5%-95% in 18 min; Column:C18) to give the title compound as a white solid (120 mg, 66%). MS (ES⁺)C₁₆H₁₆FN₇O₃S requires: 405, found: 406 [M+H]⁺.

Step 8:1-(2-fluoro-4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

A solution of1-(2-fluoro-4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylicacid (41 mg, 0.10 mmol), (4-(trifluoromethyl)pyridin-2-yl)methanamine(18 mg, 0.10 mmol), HATU (57 mg, 0.15 mmol) and K₂CO₃ (42 mg, 0.30 mmol)in DMF (1 mL) was stirred at RT for 16 h. The mixture was purified bypreparative HPLC (Mobile phase: A=0.1% ammonium hydroxide/H₂O,B=acetonitrile; Gradient: B=5%-95% in 18 min; Column: C18) to afford thetitle compound as a white solid (25 mg, 45%). MS (ES⁺) C₂₃H₂₁F₄N₉O₂Srequires: 563, found: 564 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.83 (brs, 1H), 9.25 (t, J=6.0 Hz, 1H), 8.81 (d, J=5.0 Hz, 1H), 8.65 (m, 1H),8.61 (s, 1H), 8.06 (s, 1H), 7.74-7.62 (m, 3H), 7.54 (m, 1H) 5.06 (m,1H), 4.89-4.65 (m, 4H), 4.15 (s, 2H), 3.17 (m, 2H), 2.25-1.98 (m, 2H).

Example 397:1-(2-fluoro-4-(5-(2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide2,2,2-trifluoroacetate

Step 1: ethyl1-(2-fluoro-4-(5-(2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

To a suspension of lithium2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetate (0.104 g, 0.343mmol) and ethyl1-(4-(5-amino-1,3,4-thiadiazol-2-yl)-2-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate(0.073 g, 0.23 mmol) in DMF (2 ml) at 0° C. was added T3P® (50 wt. % inDMF, 0.55 ml, 0.86 mmol), and the mixture was stirred for 1 h at 0° C.then 1 h at RT. The resulting bright yellow-orange mixture waspartitioned between EtOAc and water, and the organic layer was washedwith water, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by SiO₂ gel chromatography (2% to 5%MeOH in DCM) to give the title compound as a yellow solid (67 mg, 49%yield). MS(ES⁺) C₂₅H₂₃F₄N₇O₄S requires: 593, found: 594 [M+H]⁺.

Step 2:1-(2-fluoro-4-(5-(2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide2,2,2-trifluoroacetate

To a solution of ethyl1-(2-fluoro-4-(5-(2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylate(10 mg, 0.017 mmol) in 1,4-dioxane (0.2 ml) was added aq. methylamine(40% w/v, 0.10 mL, 1.3 mmol) and the mixture was stirred at 50° C. for 1h. The mixture was concentrated under reduced pressure, and the residuewas dissolved in DMSO and directly purified by mass-triggeredpreparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN;Gradient: B=30-70%; 12 min; Column: C18) to give the title compound as awhite powder (7.0 mg, 60% yield). MS (ES⁺) C₂₄H₂₂F₄N₈O₃S requires: 578,found: 579 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 12.74 (s, 1H), 8.62 (d,J=5.0 Hz, 1H), 8.51 (s, 1H), 8.48 (m, 1H), 7.87 (m, 2H), 7.82 (s, 1H),7.73 (d, J=4.7 Hz, 1H), 7.69 (t, J=8.0 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H),5.04 (m, 1H), 4.85-4.69 (m, 2H), 4.11 (s, 2H), 3.15 (m, 2H), 2.76 (d,J=4.6 Hz, 3H), 2.21-1.96 (m, 2H).

Example 250:(R)-1-(2-fluoro-4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

Step 1: (S)-2-hydroxybutane-1,4-diylbis(4-methylbenzenesulfonate)

To a cooled 0° C. solution of (S)-butane-1,2,4-triol (2.10 ml, 23.6mmol) in DCM (47 ml) was added 4-toluenesulfonyl chloride (11.2 g, 58.9mmol) followed by pyridine (5.69 ml, 70.7 mmol). The resulting mixturewas stirred at 0° C. for 12 h. The mixture was concentrated underreduced pressure and the residue was purified by SiO₂ gel chromatography(0% to 100% EtOAc in hexanes) to give the title compound as a colorlessliquid (4.98 g, 51% yield). MS (ES⁺) C₁₈H₂₂O₇S₂ requires: 414, found:415 [M+H]⁺.

Step 2: (R)-2-fluorobutane-1,4-diylbis(4-methylbenzenesulfonate)

To a cooled 0° C. solution of (S)-2-hydroxybutane-1,4-diylbis(4-methylbenzenesulfonate) (4.98 g, 12.0 mmol) in DCM (60 ml) wasadded DAST (2.39 ml, 18.1 mmol) and the resulting mixture was stirred asit warmed to RT for 4 h. The mixture was filtered through a plug of SiO₂gel, eluting with EtOAc. The filtrate was concentrated under reducedpressure to give the title compound as a red liquid (4.29 g, 85% yield).MS (ES⁺) C₁₈H₂₁FO₆S₂ requires: 416, found: 439 [M+Na]⁺.

Step 3: (R)-4-cyano-2-fluorobutyl 4-methylbenzenesulfonate

To a solution of (R)-2-fluorobutane-1,4-diylbis(4-methylbenzenesulfonate) (4.29 g, 10.3 mmol) in DMF (24 ml) wasadded KCN (0.957 g, 14.7 mmol) and the resulting mixture was stirred at80° C. for 4 h. The mixture was allowed to cool to RT, diluted withEtOAc (24 mL), and filtered through a plug of SiO₂ gel, eluting withEtOAc (50 mL). The filtrate was concentrated under reduced pressure togive the title compound as a colorless liquid (2.41 g, 86% yield). MS(ES⁺) C₁₂H₁₄FNO₃S requires: 271, found: 294 [M+Na]⁺.

Step 4: Ethyl(R)-1-(4-cyano-2-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of (R)-4-cyano-2-fluorobutyl 4-methylbenzenesulfonate (2.4g, 8.8 mmol) in DMF (8.9 ml) was added NaN₃ (0.690 g, 10.6 mmol) and theresulting mixture was stirred at 80° C. for 3 h. The reaction mixturewas allowed to cool to RT and diluted with DCM (88 ml). DIEA (0.153 ml,0.879 mmol), ethyl propiolate (1.34 ml, 13.2 mmol), and AcOH (0.050 ml,0.879 mmol) were added to the reaction mixture. Copper (I) iodide (0.084g, 0.44 mmol) was then added and the mixture was stirred for 15 h at RT.The reaction was concentrated under reduced pressure and the residue waspurified by SiO₂ gel chromatography (0% to 100% EtOAc in hexanes) togive the title compound as a pale orange solid (675 mg, 32% yield). MS(ES⁺) C₁₀H₁₃FN₄O₂ requires: 240, found: 241 [M+H]⁺.

Step 5: ethyl(R)-1-(4-(5-amino-1,3,4-thiadiazol-2-yl)-2-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate

To a suspension of (R)-ethyl1-(4-cyano-2-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate (675 mg, 2.81mmol) in TFA (14 ml) was added hydrazinecarbothioamide (307 mg, 3.37mmol) and the resulting mixture was stirred at 80° C. for 5 h. Themixture was concentrated under reduced pressure and the residue waspurified by SiO₂ gel chromatography (0% to 10% MeOH in DCM) to give thetitle compound as a pale yellow solid (550 mg, 62% yield). MS (ES⁺)C₁₁H₁₅FN₆O₂S requires: 314, found: 315 [M+H]⁺. Enantiopurity wasanalyzed by chiral SFC (30% MeOH/CO₂ with 0.5% NH₄OH, ChiralPak ICcolumn, 4.6×150 mm, 5 um, 3 mL/min), which indicated >98% ee.

Step 6: ethyl(R)-1-(2-fluoro-4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

To a 0° C. solution of (R)-ethyl1-(4-(5-amino-1,3,4-thiadiazol-2-yl)-2-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate(100 mg, 0.318 mmol) and 2-(pyridin-2-yl)acetic acid hydrochloride (61mg, 0.35 mmol) in DMF (1.59 mL) was added triethylamine (0.133 mL, 0.954mmol) and, after 5 min of stirring, T3P® (50 wt. % in DMF, 0.284 mL,0.477 mmol) was added dropwise. The resulting mixture was stirred at RTfor 15 h. The mixture was concentrated under reduced pressure and theresidue was purified by SiO₂ gel chromatography (0% to 10% MeOH in DCMwith 1% NH₄OH) to give the title compound as a yellow solid (123 mg, 89%yield). MS (ES⁺) C₁₈H₁₀FN₇O₃S requires: 433, found: 434 [M+H]⁺.

Step 7: lithium(R)-1-(2-fluoro-4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of (R)-ethyl1-(2-fluoro-4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylate(123 mg, 0.284 mmol) in MeOH (0.284 mL) and THF (1.135 mL) was added aq.LiOH (2.0 M, 0.17 mL, 0.34 mmol) and the resulting mixture was stirredat RT for 4 h. The mixture was concentrated under reduced pressure togive the title compound as a yellow solid (126 mg, >100% yield), whichwas used without further purification. MS (ES⁺) C₁₆H₁₆FN₇O₃S requires:405, found: 406 [M+H]⁺.

Step 8:(R)-1-(2-fluoro-4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

To a suspension of lithium(R)-1-(2-fluoro-4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylate(126 mg, 0.306 mmol), HATU (175 mg, 0.459 mmol), and(4-(trifluoromethyl)pyridin-2-yl)methanamine dihydrochloride (92 mg,0.37 mmol) in DMF (1.53 mL) was added DIEA (0.160 mL, 0.919 mmol) andthe resulting mixture was stirred at RT for 72 h. The mixture wasconcentrated under reduced pressure and the residue was adsorbed ontoCelite® and purified by SiO₂ gel chromatography (0% to 10% MeOH in DCMwith 1% NH₄OH) to give the title compound as a tan solid (51 mg, 30%yield). MS (ES⁺) C₂₃H₂₁F₄N₉O₂S requires: 563, found: 564 [M+H]⁺; ¹H NMR(600 MHz, DMSO-d₆) δ 12.72 (s, 1H), 9.23 (t, J=5.9 Hz, 1H), 8.81 (d,J=4.9 Hz, 1H), 8.61 (s, 1H), 8.49 (d, J=4.8 Hz, 1H), 7.77 (appar t,J=7.7 Hz, 1H), 7.71-7.60 (m, 2H), 7.40 (d, J=7.8 Hz, 1H), 7.29 (appar t,J=6.3 Hz, 1H), 5.08 (m, 1H), 4.89-4.70 (m, 2H), 4.67 (d, J=6.0 Hz, 2H),4.01 (s, 2H), 3.22-3.10 (m, 2H), 2.26-1.98 (m, 2H).

Example 80:N-(3-(trifluoromethoxy)benzyl)-1-(4-(4-(((5-(trifluoromethyl)pyridin-3-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

Step 1: 4-hydroxybutyl Benzoate

To a stirred solution of 1,4-butanediol (82.60 mL, 931.2 mmol) and TEA(43.26 mL, 310.4 mmol) in DCM (750 mL) at 0° C. was added benzoylchloride (36 mL, 31 mmol). The resulting mixture was allowed to warm toRT and stirred for 6 h before quenching with sat. aq. NaHCO₃ (150 mL).Layers were separated and the aqueous layer was extracted with DCM(2×100 mL). The combined organic layers were washed with sat. aq. NH₄Cl(150 mL) and water (150 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (9% to 50% EtOAc in hexanes) to give the titlecompound as a colorless oil (49.6 g; 82% yield). MS (ES⁺) C₁₁H₁₄O₃requires: 194, found: 195 [M+H]⁺.

Step 2: 4-methylsulfonyloxybutyl Benzoate

To a stirred solution of 4-hydroxybutyl benzoate (20.0 g, 103 mmol) andTEA (28.70 mL, 205.9 mmol) in DCM (300 mL) at 0° C. was addedmethanesulfonyl chloride (11.95 mL, 154.5 mmol). The resulting mixturewas allowed to warm to RT and stirred for 6 h before quenching with sat.aq. NaHCO₃ (120 mL). The layers were separated and the aqueous layer wasextracted with CH₂Cl₂ (2×60 mL). The combined organic layers were thenwashed with sat. aq. NaCl (150 mL×2), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to obtain the title compound as acolorless oil (28.02 g; 100% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.91-1.93(m, 4H), 3.01 (s, 3H), 4.29-4.38 (m, 4H), 7.42-8.04 (m, 5H).

Step 3: 4-azidobutyl Benzoate

4-methylsulfonyloxybutyl benzoate (42.06 g, 154.4 mmol) was dissolved inDMF (300 mL). NaN₃ (20.28 g, 308.9 mmol) was added cautiously. Thesolution was slowly heated to 65° C. and stirred for 16 h. The mixturewas allowed to cool to RT, transferred to a separation funnel anddiluted with Et₂O (600 mL), then washed with water (3×90 mL). Theorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure to give the title compound as a yellow oil, which wasused without further purification (33.86 g; 100% yield). ¹H NMR (400MHz, CDCl₃) δ 1.74-1.89 (m, 4H), 3.37 (t, 2H), 4.35 (t, 2H), 7.42-8.05(m, 5H).

Step 4: tert-butyl 1-(4-benzoyloxybutyl)triazole-4-carboxylate

To a solution of1-(4-azidobutyl)-N-[[3-(trifluoromethoxy)phenyl]methyl]triazole-4-carboxamide(12.0 g, 54.7 mmol) in t-BuOH (100 mL) and water (100 mL) were addedCuSO₄.5H₂O (1.38 g, 5.47 mmol), L-ascorbic acid sodium salt (2.20 g,11.0 mmol) and tert-butyl prop-2-ynoate (8.29 g, 65.7 mmol). Thesuspension was stirred vigorously at RT for 16 h. The mixture wasconcentrated under reduced pressure to remove the organic layer, dilutedwith ice-cold water, and precipitate was isolated by filtration, washedwith water and dried to give the title compound as a light brown solid(18.1 g; 96% yield). MS (ES⁺) C₁₈H₂₃N₃O₄ requires: 345, found: 346[M+H]+.

Step 5: tert-butyl 1-(4-hydroxybutyl)triazole-4-carboxylate

To a solution of tert-butyl 1-(4-benzoyloxybutyl)triazole-4-carboxylate(31 g; 90 mmol) in MeOH (300 mL) was added K₂CO₃ (12.40 g, 89.75 mmol).The mixture was stirred at RT for 4 h, filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (2% to 10% MeOH in DCM) to give the title compound asa light yellow oil (9.27 g, 43% yield). MS (ES⁺) C₁₁H₁₉N₃O₃ requires:241, found: 242 [M+H]+.

Step 6: tert-butyl 1-(4-methylsulfonyloxybutyl)triazole-4-carboxylate

To a stirred solution of tert-butyl1-(4-hydroxybutyl)triazole-4-carboxylate (8.8 g, 36 mmol) and TEA (10.17mL, 72.94 mmol) in DCM (120 mL) at 0° C. was added methanesulfonylchloride (4.23 mL, 54.7 mmoles). The resulting mixture was allowed towarm to RT and stirred for 30 min before quenching with sat. aq. NaHCO₃(90 mL). The layers were separated and the aqueous layer was extractedwith DCM (2×30 mL). The combined organic layers were washed with sat.aq. NaCl (80 mL), dried over MgSO₄, filtered and concentrated underreduced pressure to give the title compound as a colorless oil, whichwas used without further purification (11.27 g; 97% yield). MS (ES⁺)C₁₂H₂₁N₃O₅S requires: 319, found: 320[M+H]⁺.

Step 7: tert-butyl 1-(4-azidobutyl)triazole-4-carboxylate

Tert-butyl 1-(4-methylsulfonyloxybutyl)triazole-4-carboxylate (11.27 g,35.29 mmol) was dissolved in DMF (80 mL). NaN₃ (4.63 g, 70.6 mmol) wasadded cautiously. The solution was slowly heated to 60° C. and stirredfor 16 h. The mixture was allowed to cool to RT, transferred to aseparation funnel and diluted with Et₂O (250 mL), then washed with water(3×60 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford the title compound as ayellow oil (9.1 g; 97% yield), which was used without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ 1.61 (m, 11H), 2.03 (m, 2H),3.35 (t, 2H), 4.45 (t, 2H), 8.01 (s, 1H).

Step 8: methyl1-(4-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of tert-butyl 1-(4-azidobutyl)triazole-4-carboxylate (9.1g, 34 mmol) in t-BuOH (40 mL) and water (40 mL) were added CuSO₄.5H₂O(862 mg, 3.42 mmol), L-ascorbic acid sodium salt (1.37 g, 6.83 mmol) andmethyl prop-2-ynoate (2.87 g, 34.2 mmol). The suspension was stirredvigorously at RT for 16 h. The mixture was concentrated under reducedpressure to remove the organic layer, diluted with ice-cold water, andprecipitate was isolated by filtration, washed with water and dried togive the title compound as a solid (9.64 g; 81% yield). MS (ES⁺)C₁₅H₂₂N₆O₄ requires: 350, found: 351 [M+H]⁺.

Steps 9 to 12

Step 9:1-(4-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylicacid

To a 0° C. solution of tert-butyl1-(4-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylate(1.00 g, 2.85 mmol) in DCM (28 ml) was added dropwise TFA (4.40 mL, 57.1mmol), and the resulting mixture was stirred at RT for 4 h. The mixturewas concentrated under reduced pressure, azeotroping with toluene (3×25mL), to give crude title compound, which was used without furtherpurification. MS (ES⁺) C₁₁H₁₄N₆O₄ requires: 294, found: 295 [M+H]⁺.

Step 10: methyl1-(4-(4-((3-(trifluoromethoxy)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of crude1-(4-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylicacid (840 mg, 2.85 mmol) in DMF (28 mL) were added(3-(trifluoromethoxy)phenyl)methanamine (0.650 mL, 3.43 mmol), HATU (1.3g, 3.4 mmol), and DIEA (0.750 mL, 4.28 mmol). The resulting mixture wasstirred at RT for 16 h. Precipitated solid was collected by filtrationto give the title compound as an off-white powder (700 mg, 52% yield).MS (ES⁺) C₁₉H₂₀F₃N₇O₄ requires: 467, found: 468 [M+H]⁺.

Step 11:1-(4-(4-((3-(trifluoromethoxy)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylicacid

To a solution of methyl1-(4-(4-((3-(trifluoromethoxy)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylate(100 mg, 0.214 mmol) in THF (1.8 mL) and water (0.18 mL) was added LiOH(51 mg, 2.1 mmol), and the resulting mixture was stirred at RT for 4 h.The solution was neutralized with HCl in MeOH (1.25 M, 1.7 mL, 2.12mmol) and the mixture was concentrated under reduced pressure underreduced pressure to give the crude title compound as a white solid (96mg, 99%), which was used as is. MS (ES⁺) C₁₈H₁₈F₃N₇O₄ requires: 453,found: 454 [M+H]⁺.

Step 12:N-(3-(trifluoromethoxy)benzyl)-1-(4-(4-(((5-(trifluoromethyl)pyridin-3-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of1-(4-(4-((3-(trifluoromethoxy)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylicacid (194 mg, 0.428 mmol) in DMF (4.3 mL) were added(5-(trifluoromethyl)pyridin-3-yl)methanamine dihydrochloride (117 mg,0.471 mmol), HATU (244 mg, 0.642 mmol) and DIEA (0.262 mL, 1.49 mmol).The resulting mixture was stirred at RT for 18 h. Precipitated solid wascollected by filtration and rinsed with MeOH to give the title compoundas a white solid (180 mg, 69% yield). MS (ES⁺) C₂₅H₂₃F₆N₉O₃ requires:611, found: 612.5 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 9.27 (t, J=6.2 Hz,1H), 9.19 (t, J=6.3 Hz, 1H), 8.89-8.82 (m, 2H), 8.61 (s, 1H), 8.60 (s,1H), 8.12 (appar t, J=2.1 Hz, 1H), 7.45 (appar t, J=7.9 Hz, 1H), 7.34(m, 1H), 7.28 (m, 1H), 7.24 (m, 1H), 4.56 (d, J=6.1 Hz, 2H), 4.50-4.39(m, 6H), 1.87-1.77 (m, 4H).

Example 475:1-(3-fluoro-4-(4-((4-(trifluoromethyl)pyridin-2-yl)methylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

Step 1: methyl1-(3-fluoro-4-(tosyloxy)butyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of 2-fluorobutane-1,4-diyl bis(4-methylbenzenesulfonate) (20g, 48 mol), NaN₃ (3.1 g, 48 mmol), and DMF (100 ml) was stirred at 60°C. for 16 h, then water (500 mL) was added. The mixture was extractedwith DCM (800 mL), and the organic layer was concentrated under reducedpressure. To the residue was added 1:1 v: v t-BuOH/water (200 mL),methyl propiolate (4.0 g, 48 mmol), CuSO₄ (1.2 g, 7.5 mmol), andL-ascorbic acid (2.4 g, 14 mmol). The mixture was stirred at RT for 16h, then concentrated under reduced pressure. To the residue was addedwater (150 mL), the mixture was stirred for 30 min, and precipitate wasisolated by filtration to give the title compound as a white solid (12g, 60%). MS (ES⁺) C₁₅H₁₈FN₃O₅S requires: 371, found: 372 [M+H]⁺.

Step 2: tert-butyl1-(2-fluoro-4-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of methyl1-(3-fluoro-4-(tosyloxy)butyl)-1H-1,2,3-triazole-4-carboxylate (8.9 g,24 mmol), NaN₃ (1.56 g, 24.0 mmol), and DMF (50 ml) was stirred at 80°C. for 16 h, then water (500 mL) was added. The mixture was extractedwith DCM (600 mL), and the organic layer was concentrated under reducedpressure. To the residue was added 1:1 v: v t-BuOH/water (200 mL),tert-butyl propiolate (3.0 g, 24 mmol), CuSO₄ (0.60 g, 3.8 mmol), andL-ascorbic acid (1.2 g, 6.8 mmol). The mixture was stirred at RT for 16h then concentrated under reduced pressure. To the residue was addedwater (150 ml), the mixture was stirred for 30 min, and precipitate wasisolated by filtration to give the title compound as a white solid (7 g,80%). MS (ES⁺) C₁₅H₂₁FN₆O₄ requires: 368, found: 369 [M+H]⁺.

Step 3:1-(2-fluoro-4-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylicacid

A mixture of tert-butyl1-(2-fluoro-4-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylate(1.0 g, 2.7 mmol) and 1:1 v: v TFA/DCM (20 ml) was stirred at RT for 3h, then concentrated under reduced pressure. To the residue was addedwater (100 ml), the mixture was stirred for 20 min, and precipitate wasisolated by filtration to give the title compound as a white solid (500mg, 64%). MS (ES⁺) C₁₁H₁₃FN₆O₄ requires: 312, found: 313 [M+H]⁺.

Step 4: methyl1-(3-fluoro-4-(4-((4-(trifluoromethyl)pyridin-2-yl)methylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of 1-(2-fluoro-4-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylic acid (500 mg, 1.6 mmol),(4-(trifluoromethyl)pyridin-2-yl) methanamine (282 mg, 1.60 mmol), HATU(912 mg, 2.4 mmol), DIEA (600 mg, 4.8 mmol), and DMF (5 ml) was stirredat RTf or 2 h, then water (100 mL) was added and the mixture was stirredfor 10 min. Precipitate was isolated by filtration to give the titlecompound as a light brown solid (700 mg, 90%). MS (ES⁺) C₁₈H₁₈F₄N₈O₃requires: 470, found: 471[M+H]⁺.

Step 5:1-(3-fluoro-4-(4-((4-(trifluoromethyl)pyridin-2-yl)methylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylicacid

A mixture of methyl1-(3-fluoro-4-(4-((4-(trifluoromethyl)pyridin-2-yl)methylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylate(700 mg, 1.4 mmol), LiOH (70 mg, 2.8 mmol), and 1:1 v: v THF/H₂O (8 ml)was stirred at RT for 3 h, then concentrated under reduced pressure toremove organics. The pH value was adjusted to 4.0 with 1 M aq. HCl.Precipitate was isolated by filtration to give the title compound as awhite solid (600 mg, 91%). MS (ES⁺) C₁₇H₁₆F₄N₈O₃ requires: 456, found:457[M+H]⁺.

Step 6:1-(3-fluoro-4-(4-((4-(trifluoromethyl)pyridin-2-yl)methylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

A mixture of1-(3-fluoro-4-(4-((4-(trifluoromethyl)pyridin-2-yl)methylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylicacid (40 mg, 0.085 mmol), methylamine hydrochloride (6 mg, 0.09 mmol),HATU (50 mg, 0.13 mmol), DIEA (33 mg, 0.26 mmol), and DMF (1 ml) wasstirred at RT for 16 h, then purified by preparative HPLC (Mobile phase:A=0.1% ammonium hydroxide/H₂O, B=acetonitrile; Gradient: B=5%-95% in 18min; Column: C18) to afford the title compound as a white solid (26 mg,60%). MS (ES⁺) C₁₈H₁₉F₄N₉O₂ requires: 469, found: 470 [M+H]⁺. ¹H NMR(400 MHz, DMSO) δ 9.24 (t, J=6.0 Hz, 1H), 8.81 (d, J=4.9 Hz, 1H), 8.60(d, J=6.5 Hz, 2H), 8.46 (m, 1H), 7.77-7.50 (m, 2H), 5.00 (m, 1H),4.89-4.71 (m, 2H), 4.65 (m, 2H), 4.59 (m, 2H), 2.76 (d, J=4.6 Hz, 3H),2.38-2.10 (m, 2H).

Example 297:1-[4-[4-[[2-(2-pyridyl)acetyl]amino]triazol-1-yl]butyl]-N-(2-pyridylmethyl)triazole-4-carboxamide

Step 1: 1-(4-(benzoyloxy)butyl)-1H-1,2,3-triazole-4-carboxylic acid

A solution of tert-butyl1-(4-(benzoyloxy)butyl)-1H-1,2,3-triazole-4-carboxylate (5 g, 14.5 mmol)in 1:1 v: v TFA/DCM (40 ml) was stirred at RT for 3 h, then concentratedunder reduced pressure. Water (30 ml) was added, the mixture was stirredfor 15 min, and precipitate was isolated by filtration thenrecrystallized from acetonitrile/water to afford the presumed titleproduct as a white solid (3.8 g, 90%).

Step 2: 4-(4-(pyridin-2-ylmethylcarbamoyl)-1H-1,2,3-triazol-1-yl)butylBenzoate

To a stirred solution of1-(4-(benzoyloxy)butyl)-1H-1,2,3-triazole-4-carboxylic acid (1.00 g,3.46 mmol) in DMF (10 mL) were added HATU (1.84 g, 4.84 mmol), DIEA(1.21 mL, 6.91 mmol) and 2-pyridinemethanamine (449 mg, 4.15 mmol). Thereaction mixture was stirred at RT for 16 h. Water (90 mL) was added andprecipitate was isolated by filtration, washed with water, and dried togive the title compound as a brown solid (1.27 g; 97% yield). MS (ES⁺)C₂₀H₂₁N₅O₃ requires: 379, found: 380 [M+H]⁺.

Step 3:1-(4-hydroxybutyl)-N-(pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of4-(4-(pyridin-2-ylmethylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl benzoate(1.27 g, 3.35 mmol) in MeOH (80 mL) was added K₂CO₃ (463 mg, 3.35 mmol).The suspension was stirred vigorously at RT for 3 d. The reactionmixture was extracted with DCM (3×45 mL), and the combined organiclayers were dried over MgSO₄, filtered through of Celite® andconcentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (25% EtOAc in petroleum ether) to give the titlecompound as a white solid (0.86 g, 93% yield). MS (ES⁺) C₁₃H₁₇N₅O₂requires: 275, found: 276[M+H]⁺.

Step 4: 4-[4-(2-pyridylmethylcarbamoyl)triazol-1-yl]butylmethanesulfonate

To a stirred solution of1-(4-hydroxybutyl)-N-(2-pyridylmethyl)triazole-4-carboxamide (0.85 g;3.1 mmol) and TEA (0.861 mL, 6.17 mmol) in DCM (20 mL) at 0° C. wasadded methanesulfonyl chloride (0.358 mL, 14.6 mmol). The resultingmixture was allowed to warm to RT and stirred for 30 min beforequenching with sat. aq. NaHCO₃ (150 mL). Layers were separated and theaqueous layer was extracted with DCM (2×60 mL). The combined organiclayers were washed with sat. aq. NaCl (150 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the titlecompound as a colorless oil (1.09 g; 100% yield). MS (ES⁺) C₁₄H₁₉N₅O₄Srequires: 353, found: 354 [M+H]⁺.

Step 5: 1-(4-azidobutyl)-N-(2-pyridylmethyl)triazole-4-carboxamide

4-[4-(2-Pyridylmethylcarbamoyl)triazol-1-yl]butyl methanesulfonate (1.09g, 3.08 mmol) was dissolved in DMF (15 mL). NaN₃ (405 mg, 6.17 mmol) wasadded cautiously. The solution was slowly heated to 65° C. and stirredfor 16 h, then allowed to cool to RT. The mixture was transferred to aseparation funnel and diluted with Et₂O (90 mL), then washed with water(3×30 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the title compound as ayellow solid (0.9 g; 97% yield). MS (ES⁺) C₁₃H₆N₈O requires: 300, found:301 [M+H]⁺.

Step 6:1-(4-(4-(1,3-dioxoisoindolin-2-yl)-1H-1,2,3-triazol-1-yl)butyl)-N-(pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of1-(4-azidobutyl)-N-(pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide(900 mg, 3 mmol) in t-BuOH (10 mL) and water (10 mL) were addedCuSO₄.5H₂O (75.6 mg, 0.303 mmol), L-ascorbic acid sodium salt (120 mg,0.600 mmol) and 2-ethynylisoindoline-1,3-dione (513 mg, 3.00 mmol). Thissuspension was stirred vigorously at RT for 16 h, then concentratedunder reduced pressure to remove the organic layer. The mixture wasdiluted with ice-cold water, and precipitate was isolated by filtration,washed with water, and dried to give the title compound as a solid (1.28g, 91% yield). MS (ES⁺) C₂₃H₂₁N₉O₃ requires: 471, found: 472 [M+H]⁺.

Step 7:1-(4-(4-amino-1H-1,2,3-triazol-1-yl)butyl)-N-(pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide

To a suspension of1-(4-(4-(1,3-dioxoisoindolin-2-yl)-1H-1,2,3-triazol-1-yl)butyl)-N-(pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide(1.28 g, 2.71 mmol) in MeOH (45 mL) was added hydrazine monohydrate(0.660 mL, 13.6 mmol). The mixture was stirred at 60° C. for 30 min,then concentrated under reduced pressure to obtain a solid, which waswashed with cold water (3×15 mL) to give the title compound as a brownsolid (0.574 g, 62% yield). MS (ES⁺) C₁₅H₁₉N₉O requires: 341, found: 342[M+H]⁺.

Step 8:1-[4-[4-[4-[2-(2-pyridyl)acetyl]amino]triazol-1-yl]butyl]-N-(2-pyridylmethyl)triazole-4-carboxamide

To a solution of 2-pyridylacetic acid hydrochloride (27.9 mg, 0.159mmol), HATU (77.5 mg, 0.197 mmol) and DIEA (0.460 mL, 0.264 mmol) in DMF(1 mL) was added1-(4-(4-amino-1H-1,2,3-triazol-1-yl)butyl)-N-(pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide(45.0 mg, 0.131 mmol), and the resulting mixture was stirred at RT for16 h. The mixture was directly purified by preparative HPLC (Mobilephase: A=0.1% ammonium hydroxide/H₂O, B=acetonitrile; Gradient: B=5%-95%in 18 min; Column: C18) to give the title compound as a white solid (15mg; 25% yield). MS (ES⁺) C₂₂H₂₄N₁₀O₂ requires: 460, found: 461 [M+H]⁺;¹H NMR (400 MHz, MeOH-d₄) δ 8.52 (m, 2H), 8.40 (s, 1H), 8.12 (s, 1H),7.82 (m, 2H), 7.53-7.26 (m, 4H), 4.71 (s, 2H), 4.51-4.43 (m, 4H), 3.96(m, 2H), 1.94 (appar s, 4H).

Example 332:1-(4-(4-(2-(4,4-difluoropiperidin-1-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

Step 1:4-(4-(3-(trifluoromethoxy)benzylcarbamoyl)-1H-1,2,3-triazol-1-yl)butylBenzoate

A mixture of 1-(4-(benzoyloxy)butyl)-1H-1,2,3-triazole-4-carboxylic acid(1.0 g, 3.5 mmol), (3-(trifluoromethoxy)phenyl)methanamine (0.66 g, 3.5mmol), HATU (1.9 g, 5.2 mmol), and DIEA (1.3 g, 10 mmol) in DMF (10 ml)was stirred at RT for 16 h. Water (100 ml) was added, the mixture wasstirred for 10 min, and precipitate was isolated by filtration to givethe title compound as a white solid (1 g, 62%). MS (ES⁺) C₂₂H₂₁F₃N₄O₄requires: 462, found: 463 [M+H]⁺.

Step 2:1-(4-hydroxybutyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of4-(4-(3-(trifluoromethoxy)benzylcarbamoyl)-1H-1,2,3-triazol-1-yl)butylbenzoate (1.0 g, 2.2 mmol) and LiOH H₂O (0.27 g, 6.6 mmol) in THF (5 ml)and water (5 ml) was stirred at RT for 16 h, then extracted with EtOAc(50 mL). The combined organic layers were concentrated under reducedpressure to afford the title compound as a white solid (600 mg, 77%). MS(ES⁺) C₁₅H₁₇F₃N₄O₃ requires: 358, found: 359 [M+H]⁺.

Step 3:1-(4-azidobutyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

To a stirred solution of1-(4-hydroxybutyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide(600 mg, 1.68 mmol) and TEA (340 mg, 3.36 mmol) in DCM (5 ml) at RT wasadded methanesulfonyl chloride (240 mg, 2.1 mmol) in DCM (5 ml)dropwise. The mixture was stirred at RT for 30 min then treated withwater (10 ml) and extracted with DCM (20 ml). The organic layer wasconcentrated under reduced pressure to afford a white solid (presumedcrude4-(4-(3-(trifluoromethoxy)benzylcarbamoyl)-1H-1,2,3-triazol-1-yl)butylmethanesulfonate), which was dissolved in DMF (3 mL). To the solutionwas added NaN₃ (110 mg, 1.68 mmol), and the mixture was stirred at 80°C. for 1 hr, then allowed to cool to RT. Water (20 ml) was added, themixture was stirred for 15 min, and precipitate was isolated byfiltration to give the title compound as a white solid (600 mg, 93%). MS(ES⁺) C₁₅H₁₆F₃N₇O₂ requires: 383, found: 384 [M+H]⁺.

Step 4:1-(4-(4-(1,3-dioxoisoindolin-2-yl)-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of1-(4-azidobutyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide(600 mg, 0.78 mmol), 2-ethynylisoindoline-1,3-dione (133 mg, 0.780mmol), L(+)-ascorbic acid (40 mg, 0.23 mmol), and CuSO₄ (20 mg, 0.12mmol) in 1:1 v: v t-BuOH/H₂O (10 mL) was stirred at RT for 16 h, thenconcentrated under reduced pressure. Water (30 ml) was added, themixture was stirred for 15 min, and precipitate was isolated byfiltration to give the title compound as a white solid (600 mg, 71%). MS(ES⁺) C₂₅H₂₁F₃N₈O₄ requires: 554, found: 555 [M+H]⁺.

Step 5:1-(4-(4-amino-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of1-(4-(4-(1,3-dioxoisoindolin-2-yl)-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide(500 mg, 0.90 mmol) and hydrazine hydrate (90 mg, 1.8 mmol) in MeOH (10ml) was stirred at RT for 3 h, then concentrated under reduced pressure.To the residue was added EtOAc (50 mL), and the mixture was stirred for15 min, filtered, and the filtrate was concentrated under reducedpressure to give the title compound as a white solid (300 mg, 86%). MS(ES⁺) C₁₇H₁₉F₃N₈O₂ requires: 424, found: 425 [M+H]⁺.

Step 6:1-(4-(4-(2-chloroacetamido)-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of1-(4-(4-amino-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide(300 mg, 0.705 mmol), 2-chloroacetyl chloride (120 mg, 1.06 mmol) andDIEA (177 mg, 1.41 mmol) in DMF (5 ml) was stirred at RT for 2 h. Water(50 ml) was added, the mixture was stirred for 10 min, and precipitatewas isolated by filtration to give the title compound as a yellow solid(220 mg, 63%). MS (ES⁺) C₁₉H₂OClF₃N₈O₃ requires: 501, found: 502 [M+H]⁺.

Step 7:1-(4-(4-(2-(4,4-difluoropiperidin-1-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of1-(4-(4-(2-chloroacetamido)-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide(30 mg, 0.06 mmol), 3-fluoroazetidine (7 mg, 0.09 mmol) and K₂CO₃ (25mg, 0.18 mmol) in DMF (1 ml) was stirred at 65° C. for 2 h. Precipitatewas isolated by filtration and purified by preparative HPLC (Mobilephase: A=0.1% ammonium hydroxide/H₂O, B=acetonitrile; Gradient: B=5%-95%in 18 min; Column: C18) to afford the title compound as a white solid(12.7 mg, 57%). MS (ES⁺) C₂₄H₂₈F₅N₉O₃ requires: 585, found: 586 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 1.78 (m, 4H), 2.24 (m, 4H), 3.16 (m, 4H),3.90 (m, 2H), 4.40-4.49 (m, 6H), 7.24 (d, J=8.4 Hz, 1H), 7.29 (s, 1H),7.35 (d, J=7.6 Hz, 1H), 7.46 (appar t, J=8.0 Hz, 1H), 8.20 (s, 1H), 8.59(s, 1H), 9.20 (t, J=6.0 Hz, 1H), 11.45 (br s, 1H).

Example 347:1-(3-fluoro-4-(4-(2-(pyridin-2-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

Step 1: 1,4-dibromo-2-fluorobutane

To a solution of 1,4-dibromobutan-2-ol (10 g, 43 mmol) in DCM (140 mL)at 0° C. was slowly added DAST (13.9 g, 86.2 mmol). The mixture wasstirred at RT for 16 h, then carefully quenched with sat. aq. NaHCO. Themixture was extracted with DCM (3×100 mL), and the combined organiclayers were dried and concentrated under reduced pressure to give thepresumed title compound (9.5 g, 94%) as a yellow oil.

Step 2: tert-butyl1-(4-bromo-3-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of 1,4-dibromo-2-fluorobutane (5.0 g, 21 mmol) and NaN₃ (1.32g, 20.3 mmol) in DMF (10 mL) was stirred at 70° C. for 1 h then allowedto cool to RT. DCM (100 mL) was added, followed by AcOH (130 mg, 2.14mmol), DIEA (280 mg, 2.14 mmol), tert-butyl propiolate (4.04 g, 32.1mmol) and copper(I) iodide (203 mg, 1.10 mmol). The mixture was stirredat RT for 5 h, diluted with water, and extracted with DCM (2×80 mL). Thecombined organic layers were dried and concentrated under reducedpressure, and solid was washed with Et₂O and isolated by filtration togive the title compound as a brown solid (3.5 g, 51%). MS (ES⁺)C₁₁H₁₇BrFN₃O₂ requires: 321/323, found: 322/324[M+H]⁺.

Step 3: tert-butyl1-(4-(4-(1,3-dioxoisoindolin-2-yl)-1H-1,2,3-triazol-1-yl)-3-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of tert-butyl1-(4-bromo-3-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate (1.0 g, 3.1mmol) and NaN₃ (400 mg, 6.2 mmol) in DMF (2 mL) was stirred at 70° C.for 16 h, then allowed to cool to RT. DCM (20 mL) was added, followed byAcOH (19 mg, 0.31 mmol), DIEA (40 mg, 0.31 mmol),2-ethynylisoindoline-1,3-dione (640 mg, 3.73 mmol) and copper(I) iodide(30 mg, 0.16 mmol). The mixture was stirred at RT for 5 h, then dilutedwith water and treated with sat. aq. NH₄OH (2 mL). The mixture wasextracted with EtOAc (3×30 mL). The combined organic layers were driedand concentrated under reduced pressure to give the title compound as ayellow oil (1.3 g, 92%). MS (ES⁺) C₂₁H₂₂FN₇O₄ requires: 455, found: 456[M+H]⁺.

Step 4: tert-butyl1-(4-(4-amino-1H-1,2,3-triazol-1-yl)-3-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate

Hydrazine hydrate (715 mg, 14.3 mmol) was added to a solution oftert-butyl1-(4-(4-(1,3-dioxoisoindolin-2-yl)-1H-1,2,3-triazol-1-yl)-3-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate(1.3 g, 2.9 mmol) in MeOH (15 mL). The mixture was stirred at RT for 1h, then concentrated under reduced pressure and the residue purified bySiO₂ gel chromatography (10% MeOH in DCM) to give the title compound asa yellow solid (650 mg, 70%). MS (ES⁺) C₁₃H₂OFN₇O₂ requires: 325, found:326 [M+H]⁺.

Step 5: tert-butyl1-(3-fluoro-4-(4-(2-(pyridin-2-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of tert-butyl1-(4-(4-amino-1H-1,2,3-triazol-1-yl)-3-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate(350 mg, 1.08 mmol), 2-(pyridin-2-yl)acetic acid (220 mg, 1.62 mmol),HATU (614 mg, 1.62 mmol) and DIEA (209 mg, 1.62 mmol) in DMF (10 mL) wasstirred at RT for 2 h. The mixture was diluted with water and extractedwith 10:1 v: v DCM/MeOH. The organic layer was dried and concentratedunder reduced pressure to afford the title compound as a brown oil (500mg, 60%). MS (ES⁺) C₂₀H₂₅FN₈O₃ requires: 444, found: 445[M+H]⁺.

Step 6:1-(3-fluoro-4-(4-(2-(pyridin-2-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylicacid

TFA (2 mL) was added to a solution of tert-butyl1-(3-fluoro-4-(4-(2-(pyridin-2-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylate(500 mg, 1.13 mmol) in DCM (5 mL). The mixture was stirred at 50° C. for16 h. Water was added and the mixture was concentrated under reducedpressure to remove the organic layer. The aqueous mixture was washedwith EtOAc (3×20 mL), then concentrated under reduced pressure. Theresidue was washed with MeOH and solid was isolated by filtration togive the title compound as a beige solid (300 mg, 68%). MS (ES⁺)C₁₆H₁₇FN₈O₃ requires: 388, found: 389 [M+H]⁺.

Step 7:1-(3-fluoro-4-(4-(2-(pyridin-2-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of1-(3-fluoro-4-(4-(2-(pyridin-2-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylicacid (40 mg, 0.10 mmol), (3-(trifluoromethoxy)phenyl)methanamine (24 mg,0.12 mmol), HATU (57 mg, 0.15 mmol) and DIEA (20 mg, 0.15 mmol) in DMF(1 mL) was stirred at RT for 2 h. Water (10 mL) was added, andprecipitated solid was isolated by filtration and washed with MeOH togive the title compound as a white solid. MS (ES⁺) C₂₄H₂₃F₄N₉O₃requires: 561, found: 562[M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 11.17 (s,1H), 9.20 (t, J=6.1 Hz, 1H), 8.63 (s, 1H), 8.48 (m, 1H), 8.12 (s, 1H),7.75 (t, J=8.2 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.36 (dd, J=17.6, 7.8Hz, 2H), 7.31-7.20 (m, 3H), 4.94 (m, 1H), 4.68 (m, 2H), 4.58 (t, J=6.9Hz, 2H), 4.48 (d, J=6.2 Hz, 2H), 3.87 (s, 2H), 2.36-2.09 (m, 2H).

Example 372:1-(3-fluoro-4-(4-(2-(3-fluoroazetidin-1-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-N-(2-fluoro-5-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

Step 1: tert-butyl1-(4-(4-(2-chloroacetamido)-1H-1,2,3-triazol-1-yl)-3-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate

To a mixture of tert-butyl1-(4-(4-amino-1H-1,2,3-triazol-1-yl)-3-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate(800 mg, 2.46 mmol) and DIEA (635 mg, 4.92 mmol) in THF (10 mL) at 0° C.was added 2-chloroacetyl chloride (556 mg, 4.92 mmol). The mixture wasstirred at 0° C. for 30 min. The mixture was concentrated under reducedpressure, and the residue was partitioned between EtOAc and H₂O. Theaqueous layer was extracted with EtOAc (3×30 mL). The combined organiclayers were dried and concentrated under reduced pressure to afford thetitle compound as a yellow oil (950 mg, 96%). MS (ES⁺) C₁₅H₂₁ClFN₇O₃requires: 401, found: 402[M+H]⁺.

Step 2: tert-butyl1-(3-fluoro-4-(4-(2-(3-fluoroazetidin-1-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of tert-butyl1-(4-(4-(2-chloroacetamido)-1H-1,2,3-triazol-1-yl)-3-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate(450 mg, 1.12 mmol), 3-fluoroazetidine hydrochloride (138 mg, 1.23 mmol)and K₂CO₃ (310 mg, 2.24 mmol) in ACN (5 mL) was stirred at 70° C. for 5h. The mixture was concentrated under reduced pressure and the residuepurified by SiO₂ gel chromatography (10% MeOH in DCM) to give the titlecompound as a yellow solid (330 mg, 67%). MS (ES⁺) C₁₈H₂₆F₂N₈O₃requires: 440, found: 441[M+H]⁺.

Step 3:1-(3-fluoro-4-(4-(2-(3-fluoroazetidin-1-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylicacid

TFA (2 mL) was added to a solution of tert-butyl1-(3-fluoro-4-(4-(2-(3-fluoroazetidin-1-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylate(330 mg, 0.75 mmol) in DCM (10 mL). The mixture was stirred at 50° C.for 4 h. Water was added and the mixture lyophilized to give the titlecompound as a yellow oil (350 mg, 94%). MS (ES⁺) C₁₄H₁₈F₂N₈O₃ requires:384, found: 385[M+H]⁺.

Step 8:1-(3-fluoro-4-(4-(2-(3-fluoroazetidin-1-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-N-(2-fluoro-5-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of1-(3-fluoro-4-(4-(2-(3-fluoroazetidin-1-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylicacid (40 mg, 0.1 mmol), (2-fluoro-5-(trifluoromethoxy)phenyl)methanamine(25 mg, 0.12 mmol), HATU (59 mg, 0.15 mmol) and DIEA (20 mg, 0.15 mmol)in DMF (1 mL) was stirred at RT for 2 h. Water was added, andprecipitated solid was isolated by filtration and purified bypreparatory HPLC (Mobile phase: A=0.1% ammonium hydroxide/H₂O,B=acetonitrile; Gradient: B=5%-95% in 18 min; Column: C18) to give thetitle compound as a white solid (6 mg, 10%). MS (ES⁺) C₂₂H₂₃F₆N₉O₃requires: 575, found: 576[M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 10.64 (s,1H), 9.17 (t, J=6.1 Hz, 1H), 8.64 (s, 1H), 8.16 (s, 1H), 7.36-7.30 (m,3H), 5.18 (m, 1H), 4.96 (m, 1H), 4.73-4.63 (m, 2H), 4.59 (t, J=6.9 Hz,2H), 4.50 (d, J=5.8 Hz, 2H), 3.71-3.63 (m, 2H), 3.29-3.24 (m, 4H),2.33-2.13 (m, 2H).

Non-limiting examples include the following compounds andpharmaceutically acceptable salts thereof:

TABLE 1 Synthesized Examples Ex. No. Structure Name 10

N-(propan-2-yl)-1-[4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1,3,4-thiadiazol-2- yl)butyl]-1H-1,2,3-triazole-4-carboxamide 11

N-(cyclopropylmethyl)-1-[4- (5-{2-[3-(trifluoromethoxy)phenyl]acetamido}-1,3,4- thiadiazol-2-yl)butyl]-1H-1,2,3-triazole-4-carboxamide 12

N-(oxolan-3-ylmethyl)-1-[4- (5-{2-[3-(trifluoromethoxy)phenyl]acetamido}-1,3,4- thiadiazol-2-yl)butyl]-1H-1,2,3-triazole-4-carboxamide 13

1-{4-[5-(2-phenylacetamido)- 1,3,4-thiadiazol-2-yl]butyl}-N-(2-phenylethyl)-1H-1,2,3- triazole-4-carboxamide 14

N-[2-(4-hydroxypiperidin-1-yl) ethyl]-1-{4-[5-(2-phenylacetamido)-1,3,4- thiadiazol-2-yl]butyl}-1H-1,2,3-triazole-4-carboxamide 15

N-benzyl-1-{4-[5-(2- phenylacetamido)-1,3,4-thiadiazol-2-yl]butyl}-1H-1,2,3- triazole-4-carboxamide 16

N-benzyl-[4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1,3,4-thiadiazol- 2-yl)butyl]-1H-1,2,3-triazole-4-carboxamide 17

N-(2-hydroxyethyl)-1-[4-(5- {2-[3-(trifluoromethoxy)phenyl]acetamido}-1,3,4-thiadiazol-2-yl) butyl]-1H-1,2,3-triazole-4-carboxamide 18

N-(2-phenylpropan-2-yl)-1-[4- (5-{2-[3-(trifluoromethoxy)phenyl]acetamido}-1,3,4- thiadiazol-2-yl)butyl]-1H-1,2,3-triazole-4-carboxamide 19

N-(pyridin-2-ylmethyl)-1-[4- (5-{2-[3-(trifluoromethoxy)phenyl]acetamido}-1,3,4- thiadiazol-2-yl)butyl]-1H-1,2,3-triazole-4-carboxamide 20

1-[4-(5-{2-[3- (trifluoromethoxy)phenyl] acetamido}-1,3,4-thiadiazol-2-yl)butyl}-N-{[3- (trifluoromethoxy)phenyl]methyl}-1H-1,2,3-triazole-4- carboxamide 21

N-[(1R)-2-hydroxy-1- phenylethyl]-1- [4-(5-{2-[3-(trifluoromethoxy)phenyl] acetamido}-1,3,4-thiadiazol-2-yl)butyl]-1H-1,2,3- triazole-4-carboxamide 22

N-[(2,4-dimethoxyphenyl) methyl]-1-[4-(5-{2-[3-(trifluoromethoxy)phenyl] acetamido}-1,3,4-thiadiazol-2-yl)butyl]-1H-1,2,3- triazole-4-carboxamide 23

N-[(1S)-2-hydroxy-1- phenylethyl]-1-[4-(5-{2-[3-(trifluoromethoxy)phenyl] acetamido}-1,3,4-thiadiazol-2-yl)butyl]-1H-1,2,3- triazole-4-carboxamide 24

N-(2-methylpropyl)-1-{4-[6-(2- phenylacetamido)pyridazin-3-yl]butyl}-1H-1,2,3-triazole-4- carboxamide 25

5-(4-{6-[(2S)-2-hydroxy-2- phenylacetamido]pyridazin-3-yl}butyl)-N-(2-phenylethyl)- 1,3,4-thiadiazole-2- carboxamide 26

5-{4-[6-(2-phenylacetamido) pyridazin-3-yl]butyl}-N-(2-phenylethyl)-1,3,4- thiadiazole-2-carboxamide 27

N-(2-phenylethyl)-5-(4-{6- [2-(pyridin-3-yl)acetamido[pyridazin-3-yl}butyl)- 1,3,4-thiadiazole-2-carboxamide 28

N-benzyl-5-{4-[6-(2- phenylacetamido)pyridazin-3-yl]butyl}-1,3,4-thiadiazole-2- carboxamide 29

N-benzyl-5-(4-{6-[(2S)-2- hydroxy-2-phenylacetamido]pyridazin-3-yl}butyl)-1,3,4- thiadiazole-2-carboxamide 30

N-benzyl-5-(4-{6-[2-(pyridin-3- yl)acetamido]pyridazin-3-yl}butyl)-1,3,4-thiadiazole-2- carboxamide 31

N-(2-methylpropyl)-5-[4-(6- {2-[3-(trifluoromethoxy)phenyl]acetamido}pyridazin-3-yl)butyl]- 1,3,4-thiadiazole-2-carboxamide 32

N-(pyridin-2-ylmethyl)-5-[4-(6- {2-[3-(trifluoromethoxy)phenyl]acetamido}pyridazin-3-yl)butyl]- 1,3,4-thiadiazole-2-carboxamide 33

N-(oxetan-3-ylmethyl)-5-[4-(6- {2-[3-(trifluoromethoxy)phenyl]acetamido}pyridazin-3-yl)butyl]- 1,3,4-thiadiazole-2-carboxamide 34

N-(2-hydroxy-2-methylpropyl)- 5-[4-(6-{2-[3- (trifluoromethoxy)phenyl]acetamido}pyridazin-3-yl)butyl]- 1,3,4-thiadiazole-2-carboxamide 34

N-[2-(pyrrolidin-1-yl)ethyl]-5- [4-(6-{2-[3- (trifluoromethoxy)phenyl]acetamido}pyridazin-3-yl)butyl]- 1,3,4-thiadiazole-2-carboxamide 36

N-benzyl-5-[4-(6-{2-[3- (trifluoromethoxy)phenyl]acetamido}pyridazin-3-yl) butyl]-1,3,4-thiadiazole- 2-carboxamide 37

N-(2-hydroxyethyl)-5-[4-(6- {2-[3-(trifluoromethoxy)phenyl]acetamido}pyridazin- 3-yl)butyl]-1,3,4-thiadiazole- 2-carboxamide38

5-{4-[4-(benzylcarbamoyl)- 1H-1,2,3-triazol-1-yl]butyl}-N-(propan-2-yl)-1,3,4- thiadiazole-2-carboxamide 39

5-{4-[4-(benzylcarbamoyl)- 1H-1,2,3-triazol-1-yl]butyl}-N-{[3-(trifluoromethoxy) phenyl]methyl}-1,3,4- thiadiazole-2-carboxamide40

5-{4-[4-(benzylcarbamoyl)- 1H-1,2,3-triazol-1-yl]butyl}-N-(pyridin-2-ylmethyl)-1,3,4- thiadiazole-2-carboxamide 41

5-{4-[4-(benzylcarbamoyl)- 1H-1,2,3-triazol-1-yl]butyl}-N-(2-hydroxyethyl)-1,3,4- thiadiazole-2-carboxamide 42

5-{4-[4-(benzylcarbamoyl)- 1H-1,2,3-triazol-1-yl]butyl}-N-(2-methylpropyl)-1,3,4- thiadiazole-2-carboxamide 43

N-(propan-2-yl)-5-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1,3,4-thiadiazole-2-carboxamide 44

N-(2-methylpropyl)-5-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1,3,4-thiadiazole-2-carboxamide 45

N-(2-hydroxyethyl)-5-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1,3,4-thiadiazole-2-carboxamide 46

N-{[3- (trifluoromethoxy)phenyl] methyl}-5-{4-[4-({[3-(trifluoromethoxy)phenyl] methyl}carbamoyl)-1H-1,2,3-triazol-1-yl]butyl}- 1,3,4-thiadiazole-2- carboxamide 47

N-(pyridin-2-ylmethyl)-5- {4-[4-({[3-(trifluoromethoxy)phenyl]methyl}carbamoyl)- 1H-1,2,3-triazol-1-yl]butyl}-1,3,4-thiadiazole-2- carboxamide 48

N-(2-hydroxy-2-methylpropyl)- 5-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1,3,4-thiadiazole-2-carboxamide 49

N-[2-(pyrrolidin-1-yl)ethyl]- 5-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1,3,4-thiadiazole-2-carboxamide 50

N-(oxetan-3-ylmethyl)-5- {4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1,3,4-thiadiazole-2-carboxamide 51

N-(oxetan-3-yl)-5-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1,3,4-thiadiazole-2-carboxamide 52

5-{4-[4-(benzylcarbamoyl)- 1H-1,2,3-triazol-1-yl]butyl}-N-(2-methoxyethyl)-1,3,4- thiadiazole-2-carboxamide 53

tert-butyl 4-[(4-{4-[4-({[3- (trifluoromethoxy(phenyl]methyl}-5-carbamoyl)-1H- 1,2,3-triazol-1-yl]butyl}-1H-1,2,3-triazol-1-yl)methyl] piperidine-1-carboxylate 54

ethyl N-[(1-{4-[4-({[3- (trifluoromethoxy)phenyl] methyl}carbamoyl)-1H-1,2,3-triazol-1-yl]butyl}- 1H-1,2,3-triazol-4-yl)methyl] carbamate 55

l-(4-{4-[(3- methylbutanamido)methyl]- 1H-1,2,3-triazol-1-yl}butyl)-N-{[3-(trifluoromethoxy) phenyl]methyl}-1H-1,2,3- triazole-4-carboxamide56

2-methylpropyl N-[(1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1H-1,2,3-triazol-4-yl)methyl]carbamate 57

1-(4-(4-((isopentylamino) methyl)-1H-1,2,3-triazol- 1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H- 1,2,3-triazole-4-carboxamide 58

1-(4-(4-(propionamidomethyl)- 1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)- 1H-1,2,3-triazole-4-carboxamide 59

N-(cyclopropylmethyl)-5-{4- [4-({[3-(trifluoromethoxy)phenyl]methyl}carbamoyl)- 1H-1,2,3-triazol-1-yl]butyl}-1,3,4-thiadiazole-2- carboxamide 60

N-[(6-methylpyridin-3-yl)methyl]- 5-{4-[4-({[3-(trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl]butyl}-1,3,4-thiadiazole-2- carboxamide 61

5-[4-(4-{[(6-methylpyridin-3- yl)methyl]carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N-{[3- {(trifluoromethoxy)phenyl]methyl}-1,3,4-thiadiazole-2- carboxamide 62

5-[4-(4-{[(6-methylpyridin-3- yl)methyl]carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N- (pyridin-2-ylmethyl)-1,3,4-thiadiazole-2-carboxamide 63

N-(cyclopropylmethyl)-5- [4-(4-{[(6-methylpyridin-3-yl)methyl]carbamoyl}- 1H-1,2,3-triazol-1-yl)butyl]-1,3,4-thiadiazole-2- carboxamide 64

N-[(6-methylpyridin-3-yl)methyl]- 5-[4-(4-{[(6-methylpyridin-3-yl)methyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-1,3,4-thiadiazole-2-carboxamide 65

5-(4-{4-[(pyridin-2- ylmethyl)carbamoyl]-1H-1,2,3-triazol-1-yl}butyl)-N-{[3- (trifluoromethoxy)phenyl]methyl}-1,3,4-thiadiazole-2-carboxamide 66

N-(pyridin-2-ylmethyl)- 5-(4-{4-[(pyridin-2-ylmethyl)carbamoyl)-1H-1,2,3-triazol-1- yl}butyl)-1,3,4-thiadiazole-2-carboxamide 67

N-[(6-methylpyridin-3-yl)methyl]- 5(4-{4-[(pyridin-2-ylmethyl)carbamoyl]-1H-1,2,3-triazol-1-yl} butyl)-1,3,4-thiadiazole-2-carboxamide 68

N-(cyclopropylmethyl)-5-(4-{4- [(pyridin-2-ylmethyl)carbamoyl]-1H-1,2,3-triazol-1-yl}butyl)-1,3,4- thiadiazole-2-carboxamide 69

5-(4-{4-[(cyclopropylmethyl) carbamoyl]-1H-1,2,3-triazol-1-yl}butyl)-N-(pyridin-2- ylmethyl)-1,3,4-thiadiazole-2- carboxamide 70

5-(4-{4-[(cyclopropylmethyl) carbamoyl]-1H-1,2,3-triazol-1-yl}butyl)-N-[(6- methylpyridin-3-yl)methyl]-1,3,4-thiadiazole-2-carboxamide 71

N-(pyridin-2-ylmethyl)-1-(4-{4- [(pyridin-2-ylmethyl)carbamoyl]-1H-1,2,3-triazol-1-yl}butyl)-1H- 1,2,3-triazole-4-carboxamide 72

1-[4-(4-{[(6-methylpyridin-3- yl)methyl]carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N-{[3- (trifluoromethoxy)phenyl]methyl}-1H-1,2,3-triazole-4-carboxamide 73

tert-butyl 3-{[(5-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1,3,4-thiadiazol-2-yl)formamido]methyl}azetidine-1- carboxylate 74

tert-butyl 3-[({5-[4-(4-{[(6- methylpyridin-3-yl)methyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-1,3,4-thiadiazol-2-yl}formamido)methyl] azetidine-1-carboxylate 75

5-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-1,3,4- thiadiazole-2-carboxamide 76

5-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[5-(trifluoromethyl)pyridin-3-yl]methyl}-1,3,4- thiadiazole-2-carboxamide 77

5-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-1,3,4- thiadiazole-2-carboxamide 78

5-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1,3,4- thiadiazole-2-carboxamide 79

tert-butyl 3-{[(1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazol-4-yl)formamido]methyl}azetidine-1- carboxylate 80

1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[5-(trifluoromethyl)pyridin-3-yl]methyl}-1H-1,2,3- triazole-4-carboxamide 81

1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[5-(trifluoromethyl)pyridin-3-yl]methyl}-1H-1,2,3- triazole-4-carboxamide 82

1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-1,2,3- triazole-4-carboxamide 83

N-{[3- (trifluoromethoxy)phenyl]methyl}- 1-{4-[4-({[4-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)- 1H-1,2,3-triazol-1-yl]butyl}-1H-1,2,3-triazole-4-carboxamide 84

N-(cyclopentylmethyl)-1-{4-[4-({[5- (trifluoromethoxy)pyridine-3-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1H-1,2,3-triazole-4-carboxamide 85

1-(4-{4- [(cyclobutylmethyl)carbamoyl]-1H-1,2,3-triazol-1-yl}butyl)-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4- carboxamide 86

1-(4-{4-{4-[(oxolan-3- ylmethyl)carbamoyl]-1H-1,2,3-triazol-1-yl}butyl)-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4- carboxamide 87

1-(4-{4-{4-[(oxetan-3- ylmethyl)carbamoyl]-1H-1,2,3-triazol-1-yl}butyl)-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4- carboxamide 88

1-{4-[4-(methylcarbamoyl)-1H- 1,2,3-triazol-1-yl]butyl}-N-{[4-(trifluoromethyl)pyridin-2-yl] methyl}-1H-1,2,3-triazole-4- carboxamide89

[(cyclopropylmethyl)carbamoyl]-1H- 1,2,3-triazol-1-yl}butyl)-N-{[4-(trifluoromethyl)pyridin-2-yl] methyl}-1H-1,2,3-triazole-4- carboxamide90

[(cyclohexylmethyl)carbamoyl]-1H- 1,2,3-triazol-1-yl}butyl)-N-{[4-(trifluoromethyl)pyridin-2-yl] methyl}-1H-1,2,3-triazole-4- carboxamide91

N-(oxetan-3-ylmethyl)-1-{4-[4-({[5- (trifluoromethyl)pyridin-3-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1H-1,2,3-triazole-4-carboxamide 92

N-(oxolan-2-ylmethyl)-1-{4-[4-({[5- (trifluoromethyl)pyridin-3-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1H-1,2,3-triazole-4-carboxamide 93

N-(cyclobutylmethyl)-1-{4-[4-({[5- (trifluoromethyl)pyridin-3-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1H-1,2,3-triazole-4-carboxamide 94

N-(oxan-4-ylmethyl)-1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazole-4-carboxamide 95

N-methyl-1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazole-4-carboxamide 96

1-{4-[4-(benzylcarbamoyl)-1H- 1,2,3-triazol-1-yl]butyl}-N-{[4-(trifluoromethyl)pyridin-2-yl] methyl}-1H-1,2,3-triazole-4- carboxamide97

1-{4-[4-({[3- (trifluoromethyl)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide 98

1-[4-(4-{[(1R)-1- phenylethyl]carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4- carboxamide 99

1-[4-(4-{[(1S)-1- phenylethyl]carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4- carboxamide 100

1-[4-(4-{[(1R)-2-hydroxy-1- phenylethyl]carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4- carboxamide 101

1-[4-(4-{[(1S)-2-hydroxy-1- phenylethyl]carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4- carboxamide 102

1-[4-(4-{[(2R)-7- oxabicyclo[2.2.1]heptan-2-ylmethyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-N-{[4-(trifluoromethyl)pyridin-2-yl] methyl}-1H-1,2,3-triazole-4- carboxamide103

1-[4-(4-{[(2S)-7- oxabicyclo[2.2.1]heptan-2-ylmethyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-N-{[4-(trifluoromethyl)pyridin-2-yl] methyl}-1H-1,2,3-triazole-4- carboxamide104

1-{4-[4-(cyclopentylcarbamoyl)- 1H-1,2,3-triazol-1-yl]butyl}-N-{[4-(trifluoromethyl)pyridin-2-yl] methyl}-1H-1,2,3-triazole-4- carboxamide105

1-[4-(4-{[(3- cyclopropylphenyl)methyl] carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole- 4-carboxamide 106

N-[(4-cyclopropylpyridin-2-yl) methyl]-1-{4-[4-({[3-(trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl]butyl}-1H-1,2,3-triazole-4- carboxamide 107

1-[4-(4-{[(2-chloro-5- fluorophenyl)methyl]carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N- {[4-(trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4- carboxamide 108

1-[4-(4-{[(3- methoxyphenyl)methyl]carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4- carboxamide 109

1-{4-[4-({1-[3- (trifluoromethoxy)phenyl]ethyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide 110

tert-butyl N-[(3-{[(1-{4-[4-({[4- (trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1H-1,2,3-triazol-4-yl)formamido]methyl} phenyl)methyl]carbamate 111

1-[4-(4-{[(3- chlorophenyl)methyl]carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4- carboxamide 112

1-[4-(4-{[(3- fluorophenyl)methyl]carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4- carboxamide 113

1-{4-[4-({[3- (hydroxymethyl)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide 114

1-(4-{4-(oxan-2-ylmethyl) carbamoyl]-1H-1,2,3-triazol-1-yl}butyl)-N-{[4-(trifluoromethyl) pyridin-2-yl]methyl}-1H-1,2,3-triazole-4-carboxamide 115

N-{7-oxabicyclo[2.2.1]heptan-2- ylmethyl}-1-{4-[4-({[3-(trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl]butyl}-1H-1,2,3-triazole-4- carboxamide 116

N-{7-oxabicyclo[2.2.1]heptan-2- ylmethyl}-1-{4-[4-({[3-(trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl]butyl}-1H-1,2,3-triazole-4- carboxamide 117

N-(oxan-3-ylmethyl)-1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazole-4-carboxamide 118

N-(oxan-2-ylmethyl)-1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazole-4-carboxamide 119

N-(oxan-3-ylmethyl)-1-{4-[4-({[3- (trifluoromethyl)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazole-4-carboxamide 120

N-(oxan-4-ylmethyl)-1-{4-[4-({[3- (trifluoromethyl)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazole-4-carboxamide 121

N-(oxan-2-ylmethyl)-1-{4-[4-({[3- (trifluoromethyl)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazole-4-carboxamide 122

1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[2-(trifluoromethyl)pyridin-4-yl]methyl}-1H-1,2,3- triazole-4-carboxamide 123

N-[(3-cyclopropylphenyl)methyl]- 1-{4-[4-({[6-(2-hydroxypropan-2-yl)pyridin-3-yl]methyl}carbamoyl)- 1H-1,2,3-triazol-1-yl]butyl}-1H-1,2,3-triazole-4-carboxamide 124

1-{4-[4-({[3-(pyrrolidin-1- yl)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl]butyl}-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4- carboxamide 125

1-{4-[4-({[3-(2- methoxyethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide 126

N-(pyrazin-2-ylmethyl)-1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazole-4-carboxamide 127

1-(4-{4-[(pyridazin-4- ylmethyl)carbamoyl]-1H-1,2,3-triazol-1-yl}butyl)-N-{[3- (trifluoromethoxy)phenyl]methyl}-1H-1,2,3-triazole-4-carboxamide 128

N-[(3-cyclopropylphenyl)methyl]- 1-[4-(4-{[(4-cyclopropylpyridin-2-yl)methyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-1H-1,2,3-triazole-4-carboxamide 129

N-[(3-cyclopropylphenyl)methyl]- 1-[4-(4-{[(4-cyclopropylpyridin-2-yl)methyl]carbamoyl}-1H-1,2,3- triazol-1-yl)-3-fluorobutyl]-1H-1,2,3-triazole-4-carboxamide 130

1-[2-fluoro-4-(4-{[(1S)-2-hydroxy- 1-phenylethyl]carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N-1{[4- (trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4- carboxamide 131

1-[2-fluoro-4-(4-{[(1R)-1- phenylethyl]carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4- carboxamide 132

{4-[4-({[3- (difluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide 133

1-[4-(4-{[(3- cyclopropylphenyl)methyl] carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N-{[5- (trifluoromethyl)pyridin-3-yl]methyl}-1H-1,2,3-triazole-4- carboxamide 134

1-[4-(4-{[(3- cyclopropylphenyl)methyl] carbamoyl}-1H-1,2,3-triazol-1-yl)-3-fluorobutyl]- N-[(4-cyclopropylpyridin-2-yl)methyl]-1H-1,2,3-triazole-4- carboxamide 135

1-[4-(4-{[(4-cyclopropylpyridin-2- yl)methyl]carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N-{[5- (trifluoromethyl)pyridin-3-yl]methyl}-1H-1,2,3-triazole-4- carboxamide 136

1-[4-(4-{[(2,2-dimethyl-2H-1,3- benzodioxol-5-yl)methyl]carbamoyl}-1H-1,2,3-triazol-1- yl)butyl]-N-{[5-(trifluoromethyl)pyridin-3-yl] methyl}-1H-1,2,3-triazole-4- carboxamide137

1-[4-(4-{[(2,2-dimethyl-2H-1,3- benzodioxol-5-yl)methyl]carbamoyl}-1H-1,2,3-triazol-1- yl)butyl]-N-{[4-(trifluoromethyl)pyridin-2-yl] methyl}-1H-1,2,3-triazole-4- carboxamide138

N-[(2S)-2-hydroxy-2-phenylethyl]- 1-{4-[4-({[3-(trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl]butyl}-1H-1,2,3-triazole-4- carboxamide 139

N-[(2R)-2-hydroxy-2-phenylethyl]- 1-{4-[4-({[3-(trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl]butyl}-1H-1,2,3-triazole-4- carboxamide 140

N-{[5-(trifluoromethyl)pyridin-3- yl]methyl}-1-{4-[4-({[5-(trifluoromethyl)pyridin-3- yl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl]butyl}-1H-1,2,3- triazole-4-carboxamide 141

1-{4-[4-({[4-(trifluoromethyl) pyridin-2-yl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl]butyl}-N- {[5-(trifluoromethyl)pyridin-3-yl]methyl}-1H-1,2,3-triazole-4- carboxamide 142

1-{4-[4-({[5-(trifluoromethyl) pyridin-2-yl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl]butyl}-N-{[5- (trifluoromethyl)pyridin-3-yl]methyl}-1H-1,2,3-triazole-4-\ carboxamide 143

N-{[5-(trifluoromethyl)pyridin-3- yl]methyl}-1-{4-[4-({[6-(trifluoromethyl)pyridin-3- yl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl]butyl}-1H-1,2,3- triazole-4-carboxamide 144

1-{4-[4-({[6-(trifluoromethyl) pyridin-2-yl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl]butyl}-N-{[5- (trifluoromethyl)pyridin-3-yl]methyl}-1H-1,2,3-triazole-4- carboxamide 145

1-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-3-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-1{[4-(trifluoromethyl)pyridin-2-yl] methyl}-1H-1,2,3-triazole-4- carboxamide146

N-{[5-(3,3-difluoroazetidin-1- yl)pyridin-3-yl]methyl}-1-{4-[4-({[3-(trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl]butyl}-1H-1,2,3-triazole-4- carboxamide 147

1-[4-(4-{[4-cyclopropylpyridin-2- yl)methyl]carbamoyl}-1H-1,2,3-triazol-1-yl)-3-fluorobutyl]-N-{[3- (trifluoromethoxy)phenyl]methyl}-1H-1,2,3-triazole-4-carboxamide 148

1-[4-(4-({[4-cyclopropylpyridin-2- yl)methyl]carbamoyl}-1H-1,2,3-triazol-1-yl)-2-fluorobutyl]-N-{[3- (trifluoromethoxy)phenyl]methyl}-1H-1,2,3-triazole-4-carboxamide 149

1-{2-fluoro-4-[4-({[4- yl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl]butyl}-N-methyl-1H- 1,2,3-triazole-4-carboxamide 150

1-{2-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-methyl-1H-1,2,3-triazole-4-carboxamide 151

1-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-3-1-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-methyl-1H-1,2,3-triazole-4-carboxamide 152

N-[(4-cyclopropylpyridin-2-yl) methyl]-1-{3-fluoro-4-[4-({[5-(trifluoromethyl)pyridin-3- yl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl]butyl}-1H-1,2,3- triazole-4-carboxamide 153

1-{3-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-methyl-1H-1,2,3-triazole-4-carboxamide 154

N-ethyl-1-{3-fluoro-4-[4-({[4- (trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1H-1,2,3-triazole-4-carboxamide 155

1-{3-fluoro-4-[4-({[4- (trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{imidazo[2,1-b][1,3]thiazol-6-ylmethyl}-1H- 1,2,3-triazole-4-carboxamide 156

1-{2-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[4-(trifluoromethyl)pyridin-2-yl] methyl}-1H-1,2,3-triazole-4- carboxamide157

N-methyl-1-[4-(6-{2-[3- (trifluoromethoxy)phenyl]acetamido}pyridazin-3-yl)butyl]-1H-1,2,3- triazole-4-carboxamide 158

N-{[4-(trifluoromethyl)pyridin-2- yl]methyl}-1-{4-[4-({[4-(trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl]butyl}-1H-1,2,3- triazole-4-carboxamide 159

1-[2-fluoro-4-(4-{[(4-methylpyridin- 2-yl)methyl]carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4- carboxamide 160

1-[4-(6-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}pyridazin-3-yl)butyl]-N-methyl-1H- 1,2,3-triazole-4-carboxamide 161

N-methyl-1-{4-[6-(2- phenylacetamido)pyridazin-3-yl]butyl}-1H-1,2,3-triazole-4- carboxamide 162

1-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-methyl-1H-1,2,3-triazole-4-carboxamide 163

1-(3-fluoro-4-{4-[(pyridin-2- ylmethyl)carbamoyl]-1H-1,2,3-triazol-1-yl}butyl)-N-methyl- 1H-1,2,3-triazole-4-carboxamide 164

1-[4-(4-{[(5-cyclopropylpyridin-3- yl)methyl]carbamoyl}-1H-1,2,3-triazol-1-yl)-3-fluorobutyl]-N- methyl-1H-1,2,3-triazole-4- carboxamide165

1-{4-[4-(benzylcarbamoyl)-1H- 1,2,3-triazol-1-yl]-3-fluorobutyl}-N-methyl-1H-1,2,3-triazole-4- carboxamide 166

tert-butyl N-[(3-{[(1-{2-fluoro-4- [4-(methylcarbamoyl)-1H-1,2,3-triazol-1-yl]butyl}-1H-1,2,3-triazol- 4-yl)formamido]methyl}phenyl)methyl]carbamate 167

N-methyl-1-(4-{6-[2-(pyridin-2- yl)acetamido]pyridazin-3-yl}butyl)-1H-1,2,3-triazole-4-carboxamide 168

N-(cyanomethyl)-1-{3-fluoro-4-[4- ({[2-fluoro-5-(trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl]butyl}-1H-1,2,3-triazole-4- carboxamide 169

1-(4-{6-[2-(pyridin-2- yl)acetamido]pyridazin-3-yl}butyl)-N-{[3-(trifluoromethoxy)phenyl] methyl}-1H-1,2,3-triazole-4- carboxamide170

1-(3-fluoro-4-{4-[(quinolin-3- ylmethyl)carbamoyl]-1H-1,2,3-triazol-1-yl}butyl)-N-methyl- 1H-1,2,3-triazole-4-carboxamide 171

1-(3-fluoro-4-{4-[(isoquinolin-4- ylmethyl)carbamoyl]-1H-1,2,3-triazol-1-yl}butyl)-N-methyl-1H- 1,2,3-triazole-4-carboxamide 172

tert-butyl N-[(3-{[(6-{4-[4- methylcarbamoyl)-1H-1,2,3-triazol-1-yl]butyl}pyridazin-3- yl)carbamoyl]methyl}phenyl)methyl]carbamate 173

1-[4-(6-{2-[3-(2- methoxyethoxy)phenyl]acetamido}pyridazin-3-yl)butyl]-N-methyl-1H- 1,2,3-triazole-4-carboxamide 174

1-[4-(6-acetamidopyridazin-3-yl) butyl]-N-{[3-(trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide 175

1-[4-(6-acetamidopyridazin-3-yl) butyl]-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide 176

1-[4-(6-cyclopropaneamidopyridazin- 3-yl)butyl]-N-{[3-(trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide 177

1-[4-(6-cyclopropaneamidopyridazin- 3-yl)butyl]-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide178

N-methyl-1-[4-(6-{2-[3-(morpholin- 4-yl)phenyl]acetamido}pyridazin-3-yl)butyl]-1H-1,2,3-triazole-4- carboxamide 179

N-methyl-1-(4-{6-[(2S)-2- phenylpropanamido]pyridazin-3-yl}butyl)-1H-1,2,3-triazole-4- carboxamide 180

1-(4-{6-[2-(3-chloro-2- fluorophenyl)acetamido]pyridazin-3-yl}butyl)-N-methyl-1H-1,2,3-triazole- 4-carboxamide 181

1{4-[4-({[4- (difluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl]-3- fluorobutyl}-N-methyl-1H-1,2,3-triazole-4-carboxamide 182

1-[4-(4-{[(3- cyanophenyl)methyl]carbamoyl}-1H-1,2,3-triazol-1-yl)-3-fluorobutyl]-N- methyl-1H-1,2,3-triazole-4-carboxamide 183

1-[3-fluoro-4-(4-{[(3- methanesulfonylphenyl)methyl]carbamoyl}-1H-1,2,3-triazol-1-yl) butyl]-N-methyl-1H-1,2,3-triazole-4-carboxamide 184

1-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-methyl-1H-1,2,3-triazole-4-carboxamide 185

methyl 3-{[(1-{2-fluoro-4-[4- (methylcarbamoyl)-1H-1,2,3-triazol-1-yl]butyl}-1H-1,2,3- triazol-4-yl)formamido]methyl} benzoate186

1-{3-fluoro-4-[4-({[6- (trifluoromethyl)pyridin-3-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-methyl-1H-1,2,3-triazole-4-carboxamide 187

1-[3-fluoro-4-(4-{[(6-methylpyridin- 3-yl)methyl]carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N-methyl-1H- 1,2,3-triazole-4-carboxamide 188

N-methyl-1-{4-[6-(2-{5-[3- (trifluoromethoxy)phenyl]pyridin-3-yl}acetamido)pyridazin-3-yl]butyl}- 1H-1,2,3-triazole-4-carboxamide 189

5-{3-fluoro-4-[4-(methylcarbamoyl)- 1H-1,2,3-triazol-1-yl]butyl}-N-{[5-(trifluoromethyl)pyridin-2-yl] methyl}-1,3,4-thiadiazole-2- carboxamide190

1-(4-{6-[2-(4-cyclopropylpyridin-2- yl)acetamido]pyridazin-3-yl}butyl)-N-methyl-1H-1,2,3-triazole-4- carboxamide 191

1-(4-{6-[2-(4-chloropyridin-2- yl)acetamido]pyridazin-3-yl}butyl)-N-methyl-1H-1,2,3-triazole-4- carboxamide 192

N-methyl-1-{4-[6-(2-{4-[3- (trifluoromethoxy)phenyl]pyridin-2-yl}acetamido)pyridazin-3-yl]butyl}- 1H-1,2,3-triazole-4-carboxamide 193

(S)-1-(2-fluoro-4-(5-(2-(3- (trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl) butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide 194

(S)-1-(2-fluoro-4-(5-(2-(3- (trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol- 2-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide 195

1-(2-fluoro-4-(5-(2-(5-(3- (trifluoromethoxy)phenyl)pyridin-3-yl)acetamido)-1,3,4-thiadiazol-2- yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide 196

tert-butyl 3-((5-(3-fluoro-4-(4- (methylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1,3,4- thiadiazole-2-carboxamido)methyl)piperidine-1- carboxylate 197

(S)-1-(2-fluoro-4-(5-(2-(pyridin-2- yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-(2-fluoro-5- (trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide 198

(R)-1-(2-fluoro-4-(5-(2-(pyridin-2- yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-(2-fluoro-5- (trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide 199

1-(4-(6-(2-(3-(3,6-dihydro-2H-pyran- 4-yl)phenyl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole- 4-carboxamide 200

1-(4-(6-(2-(4-bromopyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4- carboxamide 201

(R)-1-(2-fluoro-4-(5-(2-(pyridin-2- yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-((5- (trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4- carboxamide 202

1-(4-(6-(2-(5-(3,3- difluorocyclobutoxy)pyridin-3-yl)acetamido)pyridazin-3-yl)butyl)- N-methyl-1H-1,2,3-triazole-4-carboxamide 203

1-(4-(6-(2-(pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N-((4-(trifluoromethyl)pyridin-2- yl)methyl)-1H-1,2,3-triazole-4-carboxamide 204

1-(2-fluoro-4-(5-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N- (pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide 205

1-(2-fluoro-4-(5-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-((4- methoxypyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide 206

1-(2-fluoro-4-(5-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-((6- methoxypyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide 207

N-methyl-1-(4-(6-(2-(4-(2- (trifluoromethoxy)phenyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide 208

N-methyl-1-(4-(6-(2-(4-(tetrahydro- 2H-pyran-4-yl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide 209

5-(3-fluoro-4-(4-(methylcarbamoyl)- 1H-1,2,3-triazol-1-yl)butyl)-N-(3-(piperidin-1-yl)benzyl)-1,3,4- thiadiazole-2-carboxamide 210

N-methyl-1-(4-(6-(2-(4- (trifluoromethyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide 211

1-(2-fluoro-4-(6-(2-(pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N-((4-(trifluoromethyl)pyridin-2- yl)methyl)-1H-1,2,3-triazole-4-carboxamide 212

tert-butyl 4-(3-(2-((6-(4-(4- (methylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)pyridazin-3-yl)amino)-2- oxoethyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate 213

tert-butyl 4-(3-(2-((6-(4-(4- (methylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)pyridazin-3-yl)amino)-2- oxoethyl)phenyl)piperidine-1-carboxylate 214

N-methyl-1-(4-(6-(2-(2-oxopiperidin-1-yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide215

N-methyl-1-(4-(6-(2-(4- phenylpiperidin-1-yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide 216

N-methyl-5-(4-(6-(2-(5-(3- (trifluoromethoxy)phenyl)pyridin-3-yl)acetamido)pyridazin-3-yl)butyl)- 1,3,4-thiadiazole-2-carboxamide 217

N-methyl-1-(4-(6-(2-(3-(tetrahydro- 2H-pyran-4-yl)phenyl)acetamido)pyridazin-3- yl)butyl)-1H-1,2,3-triazole-4-carboxamide 218

1-(2-fluoro-4-(5-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N- (pyridin-3-ylmethyl)-1H-1,2,3-triazole-4-carboxamide 219

1-(2-fluoro-4-(5-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-((6- methoxypyridin-3-yl)methyl)-1H-1,2,3-triazole-4-carboxamide 220

(S)-5-(3-fluoro-4-(4- (methylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-N-((4- (trifluoromethyl)pyridin-2-yl)methyl)-1,3,4-thiadiazole-2- carboxamide 221

(R)-5-(3-fluoro-4-(4- (methylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-N-((4- (trifluoromethyl)pyridin-2-yl)methyl)-1,3,4-thiadiazole-2-carboxamide 222

1-(2-fluoro-4-(5-(2-(3- (trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-((5- methoxypyridin-3-yl)methyl)-1H-1,2,3-triazole-4-carboxamide 223

1-(2-fluoro-4-(5-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-((2- methoxypyridin-3-yl)methyl)-1H-1,2,3-triazole-4-carboxamide 224

methyl (6-(4-(4-(((4- (trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)-1H-1,2,3 -triazol-1-yl)butyl)pyridazin-3-yl)carbamate 225

N-methyl-1-(4-(6-(2-(4-(2,2,2- trifluoroethoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide 226

1-(2-fluoro-4-(5-(2-(4- (trifluoromethyl)pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2- yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide 227

N-methyl-1-(4-(6-(2-(2-oxo-4-(3- (trifluoromethoxy)phenyl)piperazin-1-yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide228

N-methyl-1-(4-(6-(2-(4-(3- (trifluoromethoxy)phenyl)piperazin-1-yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide229

N-methyl-5-(4-(6-(2-(4- (trifluoromethyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)- 1,3,4-thiadiazole-2-carboxamide 230

1-(4-(6-(2-(5-(3,3- difluorocyclobutoxy)pyridin-3-yl)acetamido)pyridazin-3-yl)butyl)- N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4- carboxamide 231

1-(4-(6-(2-(5-(3,3- difluorocyclobutoxy)pyridin-3-yl)acetamido)pyridazin-3-yl)butyl)- N-(pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide 232

N-methyl-1-(4-(6-(2-(4-(4- (trifluoromethoxy)phenyl)piperazin-1-yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide 233

N-methyl-1-(4-(6-(2-(4-(4- (trifluoromethoxy)phenyl)piperazin-1-yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide 234

5-(3-fluoro-4-(4-((pyridin-2- ylmethyl)carbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-N-((4- (trifluoromethyl)pyridin-2-yl)methyl)-1,3,4-thiadiazole-2- carboxamide 235

5-(3-fluoro-4-(4-(((4- (trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)-1H-1,2,3- triazol-1-yl)butyl)-N-(pyridin-2-ylmethyl)-1,3,4-thiadiazole-2- carboxamide 236

1-(4-(6-acetamidopyridazin-3-yl)-2- fluorobutyl)-N-((4-(trifluoromethyl)pyridin-2-yl) methyl)-1H-1,2,3-triazole-4- carboxamide237

1-(4-(6-(2-(3- (dimethylamino)phenyl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H- 1,2,3-triazole-4-carboxamide 238

(S)-1-(2-fluoro-4-(5-(2-(pyridin-2- yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-((4- (trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4- carboxamide 239

(S)-1-(2-fluoro-4-(5-(2-(3- (trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-methyl- 1H-1,2,3-triazole-4-carboxamide240

(R)-1-(2-fluoro-4-(5-(2-(3- (trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-methyl- 1H-1,2,3-triazole-4-carboxamide241

1-(2-fluoro-4-(6-(2-(2-oxo-4-(3- (trifluoromethoxy)phenyl)piperazin-1-yl)acetamido)pyridazin-3-yl)butyl)-N- methyl-1H-1,2,3-triazole-4-carboxamide 242

1-(2-fluoro-4-(6-(2-(4-(3- (trifluoromethoxy)phenyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N- methyl-1H-1,2,3-triazole-4-carboxamide 243

cyclohexyl (6-(4-(4- (methylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)pyridazin-3- yl)carbamate 244

1-(2-fluoro-4-(6-(2- phenylacetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole- 4-carboxamide 245

1-(4-(6-(2-(5-(3,3- difluorocyclobutoxy)pyridin-3-yl)acetamido)pyridazin-3-yl)-2- fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide 246

N-(2-hydroxyethyl)-1-(4-(6-(2-(4-(3- (trifluoromethoxy)phenyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide 247

N-methyl-1-(4-(6-(2-(2-oxo-4-(3- (trifluoromethoxy)benzyl)piperazin-1-yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide 248

1-(2-fluoro-4-(6-(2-(4- (trifluoromethyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)- N-methyl-1H-1,2,3-triazole-4-carboxamide 249

N-methyl-1-(4-(6-(2-(2-oxo-4-(2- (trifluoromethoxy)phenyl)piperazin-1-yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide 250

(R)-1-(2-fluoro-4-(5-(2-(pyridin-2- yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-((4- (trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4- carboxamide 251

1-(4-(6-(2-(4-cyclobutoxypyridin-2- yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3- triazole-4-carboxamide 252

1-(4-(6-(2-(4-(3,3- difluorocyclobutoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)-2- fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide 253

1-(2-fluoro-4-(6-(2-(4-(tetrahydro- 2H-pyran-4-yl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)- N-methyl-1H-1,2,3-triazole-4-carboxamide 254

(R)-1-(2-fluoro-4-(6-(2-(pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4- carboxamide 255

(R)-1-(2-fluoro-4-(6-(2-(4-(3- (trifluoromethoxy)phenyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)- N-methyl-1H-1,2,3-triazole-4-carboxamide 256

(S)-1-(2-fluoro-4-(6-(2-(pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4- carboxamide 257

(S)-1-(2-fluoro-4-(6-(2-(4-(3- (trifluoromethoxy)phenyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)- N-methyl-1H-1,2,3-triazole-4-carboxamide 258

N-methyl-1-(4-(6-(2-(4-(1,1,1- trifluoropropan-2-yl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide 259

(R)-1-(2-fluoro-4-(6-(2-(4- (trifluoromethyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)- N-methyl-1H-1,2,3-triazole-4-carboxamide 260

(S)-1-(2-fluoro-4-(6-(2-(4- (trifluoromethyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)- N-methyl-1H-1,2,3-triazole-4-carboxamide 261

1-(4-(6-(2-(4-(3,3- difluorocyclobutoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)- N-methyl-1H-1,2,3-triazole-4-carboxamide 262

1-(2-fluoro-4-(6-(2-(4-(2,2,2- trifluoroethoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)- N-methyl-1H-1,2,3-triazole-4-carboxamide 263

1-(4-(6-(2-(6-cyclopropyl-4- (trifluoromethyl)pyridin-2-yl)acetamido)pyridazin-3-yl)-2- fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide 264

1-(2-fluoro-4-(6-(2-(6-methyl-4- (trifluoromethyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)- N-methyl-1H-1,2,3-triazole-4-carboxamide 265

1-(2-fluoro-4-(5-(2-(4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-methyl- 1H-1,2,3-triazole-4-carboxamide266

1-(2-fluoro-4-(6-(2-(4-((1,1,1- trifluoropropan-2-yl)oxy)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)- N-methyl-1H-1,2,3-triazole-4-carboxamide 267

(R)-1-(4-(6-(2-(4- (cyclopropyldifluoromethyl)pyridin-2-yl)acetamido)pyridazin-3-yl)-2- fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide 268

(R)-1-(2-fluoro-4-(6-(2-(6-methyl-4- (trifluoromethyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)- N-methyl-1H-1,2,3-triazole-4-carboxamide 269

(R)-1-(2-fluoro-4-(6-(2-(4-(3-(2,2,2-trifluoroethoxy)cyclobutoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)- N-methyl-1H-1,2,3-triazole-4-carboxamide 270

(R)-1-(2-fluoro-4-(6-(2-(1-(3- (trifluoromethoxy)phenyl)-1H-imidazol-4-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole- 4-carboxamide 271

(R)-1-(2-fluoro-4-(6-(2-(4- ((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole- 4-carboxamide 272

(R)-1-(4-(6-(2-(4-(3,3- difluorocyclobutoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)-2- fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide 273

(R)-1-(2-fluoro-4-(6-(2- phenylacetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole- 4-carboxamide 274

1-(4-(6-(2-(4- (difluoromethoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)-2- fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide 275

(R)-1-(4-(6-(2-(4-cyclopropylpyridin- 2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3- triazole-4-carboxamide 276

1-{4-[4-(2-cyclopropylacetamido)- 1H-1,2,3-triazol-1-yl]butyl}-N-{[3-(trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide 277

1-{4-[4-(2-cyclopentylacetamido)- 1H-1,2,3-triazol-1-yl]butyl}-N-(pyridin-2-ylmethyl)-1H-1,2,3- triazole-4-carboxamide 278

1-{4-[4-(2-cyclopropylacetamido)-1H-1,2,3-triazol-1-yl]butyl}-N-(pyridin-2- ylmethyl)-1H-1,2,3-triazole-4-carboxamide 279

N-(pyridin-2-ylmethyl)-1-[4-(4-{2-[3-(trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3- triazole-4-carboxamide 280

1-{4-[4-(2-cyclohexylacetamido)-1H-1,2,3-triazol-1-yl]butyl}-N-(pyridin-2- ylmethyl)-1H-1,2,3-triazole-4-carboxamide 281

N-(cyclohexylmethyl)-1-{4-[4-(2- cyclopropylacetamido)-1H-1,2,3-triazol-1-yl]butyl}-1H-1,2,3-triazole- 4-carboxamide 282

N-(cyclohexylmethyl)-1-{4-[4-(2- cyclopentylacetamido)-1H-1,2,3-triazol-1-yl]butyl}-1H-1,2,3-triazole- 4-carboxamide 283

1-{4-[4-(2-cyclohexylacetamido)-1H- 1,2,3-triazol-1-yl]butyl}-N-(cyclohexylmethyl)-1H-1,2,3-triazole- 4-carboxamide 284

N-(cyclohexylmethyl)-1-(4-{4-[2- (pyridin-3-yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-1H-1,2,3-triazole- 4-carboxamide 285

N-(cyclohexylmethyl)-1-(4-{4-[2- (pyridin-2-yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-1H-1,2,3-triazole- 4-carboxamide 286

N-(cyclohexylmethyl)-1-[4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3- triazole-4-carboxamide 287

N-(cyclopentylmethyl)-1-{4-[4-(2- cyclopropylacetamido)-1H-1,2,3-triazol-1-yl]butyl}-1H-1,2,3-triazole- 4-carboxamide 288

1-{4-[4-(2-cyclopentylacetamido)-1H- 1,2,3-triazol-1-yl]butyl}-N-(cyclopentylmethyl)-1H-1,2,3-triazole- 4-carboxamide 289

1-{4-[4-(2-cyclohexylacetamido)-1H- 1,2,3-triazol-1-yl]butyl}-N-(cyclopentylmethyl)-1H-1,2,3- triazole-4-carboxamide 290

N-(cyclopentylmethyl)-1-(4-{4-[2- (pyridin-3-yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-1H-1,2,3-triazole- 4-carboxamide 291

N-(cyclopentylmethyl)-1-(4-{4-[2- (pyridin-2-yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-1H-1,2,3-triazole- 4-carboxamide 292

N-(cyclopentylmethyl)-1-[4-(4-{2-[3-(trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3- triazole-4-carboxamide 293

1-(4-{4-[2-(pyridin-2-yl)acetamido]- 1H-1,2,3-triazol-1-yl}butyl)-N-{[3-(trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide 294

1-(4-{4-[2-(pyridin-3-yl)acetamido]- 1H-1,2,3-triazol-1-yl}butyl)-N-{[3-(trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide 295

1-{4-[4-(2-cyclopentylacetamido)- 1H-1,2,3-triazol-1-yl]butyl}-N-{[3-(trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide 296

1-{4-[4-(2-cyclohexylacetamido)-1H- 1,2,3-triazol-1-yl]butyl}-N-{[3-(trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide 297

1-(4-{4-[2-(pyridin-2-yl)acetamido]- 1H-1,2,3-triazol-1-yl}butyl)-N-(pyridin-2-ylmethyl)-1H-1,2,3- triazole-4-carboxamide 298

N-(pyridin-2-ylmethyl)-1-(4-{4-[2- (pyridin-3-yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-1H-1,2,3-triazole- 4-carboxamide 299

N-[(6-methylpyridin-3-yl)methyl]-1- [4-(4-{2-[3-(trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3- triazole-4-carboxamide 300

1-{4-[4-(2-cyclopropylacetamido)- 1H-1,2,3-triazol-1-yl]butyl}-N-[(6-methylpyridin-3-yl)methyl]-1H- 1,2,3-triazole-4-carboxamide 301

N-(cyclopropylmethyl)-1-[4-(4-{2-[3-(trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3- triazole-4-carboxamide 302

N-(cyclopropylmethyl)-1-(4-{4-[2- (pyridin-2-yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-1H-1,2,3-triazole- 4-carboxamide 303

N-(cyclopropylmethyl)-1-(4-{4-[2- (pyridin-3-yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-1H-1,2,3-triazole- 4-carboxamide 304

1-{4-[4-(2-cyclopentylacetamido)-1H- 1,2,3-triazol-1-yl]butyl}-N-(cyclopropylmethyl)-1H-1,2,3- triazole-4-carboxamide 305

1-{4-[4-(2-cyclohexylacetamido)-1H- 1,2,3-triazol-1-yl]butyl}-N-(cyclopropylmethyl)-1H-1,2,3- triazole-4-carboxamide 306

1-(4-{4-[2-(6-methylpyridin-3- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-(pyridin-2-ylmethyl)- 1H-1,2,3-triazole-4-carboxamide 307

N-(pyridin-3-ylmethyl)-1-[4-(4-{2-[3-(trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3- triazole-4-carboxamide 308

1-{4-[4-(2-cyclopropylacetamido)-1H-1,2,3-triazol-1-yl]butyl}-N-(pyridin-3- ylmethyl)-1H-1,2,3-triazole-4-carboxamide 309

1-{4-[4-(2-cyclopentylacetamido)-1H-1,2,3-triazol-1-yl]butyl}-N-(pyridin-3- ylmethyl)-1H-1,2,3-triazole-4-carboxamide 310

1-{4-[4-(2-cyclohexylacetamido)-1H-1,2,3-triazol-1-yl]butyl}-N-(pyridin-3- ylmethyl)-1H-1,2,3-triazole-4-carboxamide 311

N-(cyclopentylmethyl)-1-(4-{4-[2-(6- methylpyridin-3-yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-1H-1,2,3- triazole-4-carboxamide 312

N-(cyclohexylmethyl)-1-(4-{4-[2-(6- methylpyridin-3-yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-1H-1,2,3- triazole-4-carboxamide 313

1-(4-{4-[2-(6-methylpyridin-3- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-{[3- (trifluoromethoxy)phenyl]methyl}-1H-1,2,3-triazole-4-carboxamide 314

N-[(6-methylpyridin-3-yl)methyl]- 1-(4-{4-[2-(pyridin-2-yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-1H- 1,2,3-triazole-4-carboxamide 315

N-[(6-methylpyridin-3-yl)methyl]- 1-(4-{4-[2-(pyridin-3-yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-1H- 1,2,3-triazole-4-carboxamide 316

1-(4-{4-[2-(6-methylpyridin-3- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-[(6-methylpyridin-3- yl)methyl]-1H-1,2,3-triazole-4-carboxamide 317

1-{4-[4-(2-cyclopentylacetamido)- 1H-1,2,3-triazol-1-yl]butyl}-N-[(6-methylpyridin-3-yl)methyl]-1H- 1,2,3-triazole-4-carboxamide 318

1-{4-[4-(2-cyclohexylacetamido)- 1H-1,2,3-triazol-1-yl]butyl}-N-[(6-methylpyridin-3-yl)methyl]-1H- 1,2,3-triazole-4-carboxamide 319

N-(cyclopropylmethyl)-1-(4-{4-[2- (6-methylpyridin-3-yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-1H- 1,2,3-triazole-4-carboxamide 320

1-(4-{4-[2-(pyridin-3-yl)acetamido]- 1H-1,2,3-triazol-1-yl}butyl)-N-(pyridin-3-ylmethyl)-1H-1,2,3- triazole-4-carboxamide 321

1-(4-{4-[2-(pyridin-2-yl)acetamido]- 1H-1,2,3-triazol-1-yl}butyl)-N-(pyridin-3-ylmethyl)-1H-1,2,3- triazole-4-carboxamide 322

1-(4-{4-[2-(6-methylpyridin-3- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-(pyridin-3-ylmethyl)- 1H-1,2,3-triazole-4-carboxamide 323

1-(4-{4-[2-(3,3-difluoroazetidin-1- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-(pyridin-2-ylmethyl)- 1H-1,2,3-triazole-4-carboxamide 324

1-(4-{4-[2-(3-fluoroazetidin-1- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-(pyridin-2-ylmethyl)- 1H-1,2,3-triazole-4-carboxamide 325

1-(4-{4-[2-(3,3-difluoropyrrolidin- 1-yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-(pyridin-2-ylmethyl)- 1H-1,2,3-triazole-4-carboxamide 326

1-(4-{4-[2-(4,4-difluoropiperidin-1- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-(pyridin-2-ylmethyl)- 1H-1,2,3-triazole-4-carboxamide 327

1-[3-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N- (pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide 328

1-[3-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-[(6- methylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxamide 329

1-(4-{4-[2-(3-fluoroazetidin-1- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-{[3- (trifluoromethoxy)phenyl]methyl}-1H-1,2,3-triazole-4-carboxamide 330

1-(4-{4-[2-(3,3-difluoroazetidin-1- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-{[3- (trifluoromethoxy)phenyl]methyl}-1H-1,2,3-triazole-4-carboxamide 331

1-(4-{4-[2-(3,3-difluoropyrrolidin-1- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-{[3- (trifluoromethoxy)phenyl]methyl}-1H-1,2,3-triazole-4-carboxamide 332

1-(4-{4-[2-(4,4-difluoropiperidin-1- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-{[3- (trifluoromethoxy)phenyl]methyl}-1H-1,2,3-triazole-4-carboxamide 333

N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}-1- [4-(4-{2-[3-(trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3- triazole-4-carboxamide 334

N-[(5-chloro-2-fluorophenyl)methyl]- 1-[4-(4-{2-[3-(trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3- triazole-4-carboxamide 335

N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}-1-(4-{4-[2-(6-methylpyridin-3- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-1H-1,2,3-triazole-4- carboxamide 336

N-[(5-chloro-2-fluorophenyl)methyl]- 1-(4-{4-[2-(6-methylpyridin-3-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-1H-1,2,3-triazole-4-carboxamide 337

N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}-1-(4-{4-[2-(pyridin-2-yl)acetamido]- 1H-1,2,3-triazol-1-yl}butyl)-1H-1,2,3-triazole-4-carboxamide 338

N-[(5-chloro-2-fluorophenyl)methyl]-1-(4-{4-[2-(pyridin-2-yl)acetamido]- 1H-1,2,3-triazol-1-yl}butyl)-1H-1,2,3-triazole-4-carboxamide 339

1-[3-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-{[3- (trifluoromethoxy)phenyl]methyl}-1H-1,2,3-triazole-4-carboxamide 340

1-[3-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-{[2- fluoro-5-(trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide 341

1-[3-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-[(3- fluoropyridin-2-yl)methyl]-1H-1,2,3-triazole-4-carboxamide 342

1-(3-fluoro-4-{4-[2-(6-methylpyridin-3-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-{[3-(trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide 343

1-(3-fluoro-4-{4-[2-(6-methylpyridin-3-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-{[2-fluoro-5-(trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide 344

1-(3-fluoro-4-{4-[2-(6-methylpyridin-3-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-(pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide 345

1-(3-fluoro-4-{4-[2-(6-methylpyridin-3-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-1,2,3-triazole-4- carboxamide 346

1-(3-fluoro-4-{4-[2-(6-methylpyridin-3-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-[(6-methylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4- carboxamide 347

1-(3-fluoro-4-{4-[2-(pyridin-2- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-{[3- (trifluoromethoxy)phenyl]methyl}-1H-1,2,3-triazole-4-carboxamide 348

1-(4-{4-[2-(3-fluoroazetidin-1- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-[(6-methylpyridin-3- yl)methyl]-1H-1,2,3-triazole-4-carboxamide 349

N-[(5-chloro-2-fluorophenyl)methyl]- 1-(4-{4-[2-(3-fluoroazetidin-1-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-1H-1,2,3-triazole-4-carboxamide 350

N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}-1-(4-{4-[2-(3-fluoroazetidin-1- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-1H-1,2,3-triazole-4- carboxamide 351

1-(4-{4-[2-(3,3-difluoroazetidin-1- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-[(6-methylpyridin-3- yl)methyl]-1H-1,2,3-triazole-4-carboxamide 352

N-[(5-chloro-2-fluorophenyl)methyl]- 1-(4-{4-[2-(3,3-difluoroazetidin-1-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-1H-1,2,3-triazole-4-carboxamide 353

1-(4-{4-[2-(3,3-difluoroazetidin-1- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}-1H-1,2,3-triazole-4-carboxamide 354

1-(4-{4-[2-(3,3-difluoropyrrolidin-1- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-[(6-methylpyridin-3- yl)methyl]-1H-1,2,3-triazole-4-carboxamide 355

N-[(5-chloro-2-fluorophenyl)methyl]-1-(4-{4-[2-(3,3-difluoropyrrolidin-1- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-1H-1,2,3-triazole-4- carboxamide 356

1-(4-{4-[2-(3,3-difluoropyrrolidin-1- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}-1H-1,2,3-triazole-4-carboxamide 357

1-(4-{4-[2-(3,3-difluoropyrrolidin-1- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-[(3-fluoropyridin-2- yl)methyl]-1H-1,2,3-triazole-4-carboxamide 358

1-(4-{4-[2-(4,4-difluoropiperidin-1- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-[(6-methylpyridin-3- yl)methyl]-1H-1,2,3-triazole-4-carboxamide 359

N-[(5-chloro-2-fluorophenyl)methyl]-1-(4-{4-[2-(4,4-difluoropiperidin-1- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-1H-1,2,3-triazole-4- carboxamide 360

1-(4-{4-[2-(4,4-difluoropiperidin-1- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}-1H-1,2,3-triazole-4-carboxamide 361

1-(4-{4-[2-(4,4-difluoropiperidin-1- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-[(3-fluoropyridin-2- yl)methyl]-1H-1,2,3-triazole-4-carboxamide 362

1-(3-fluoro-4-{4-[2-(pyridin-2- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-(pyridin-2-ylmethyl)- 1H-1,2,3-triazole-4-carboxamide 363

1-(3-fluoro-4-{4-[2-(pyridin-2- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}-1H-1,2,3-triazole-4-carboxamide 364

1-(3-fluoro-4-{4-[2-(pyridin-2- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-[(6-methylpyridin-3- yl)methyl]-1H-1,2,3-triazole-4-carboxamide 365

1-(3-fluoro-4-{4-[2-(pyridin-2- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-[(3-fluoropyridin-2- yl)methyl]-1H-1,2,3-triazole-4-carboxamide 366

1-(4-{4-[2-(4-chloro-2- fluorophenyl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-(pyridin-2- ylmethyl)-1H-1,2,3-triazole-4-carboxamide 367

1-[4-(4-{2-[2-fluoro-4- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N- (pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide 368

1-{2-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-[(6-methylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4- carboxamide 369

1-{2-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-(pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide 370

1-{3-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-[(6-methylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4- carboxamide 371

1-(3-fluoro-4-{4-[2-(3-fluoroazetidin-1-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-{[3-(trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide 372

1-(3-fluoro-4-{4-[2-(3-fluoroazetidin-1-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-{[2-fluoro-5-(trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide 373

1-{3-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-(pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide 374

1-(3-fluoro-4-{4-[2-(3-fluoroazetidin-1-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-[(6-methylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4- carboxamide 375

1-[3-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N- (pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide 376

1-[3-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-[(6- methylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxamide 377

1[3-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-{[2- fluoro-5-(trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide 378

1-[3-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-[(3- fluoropyridin-2-yl)methyl]-1H-1,2,3-triazole-4-carboxamide 379

1-[3-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-{[3- (trifluoromethoxy)phenyl]methyl}-1H-1,2,3-triazole-4-carboxamide 380

1-[4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-{[3- (trifluoromethoxy)phenyl]methyl}-1H-1,2,3-triazole-4-carboxamide 381

1-[4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-{[2- fluoro-5-(trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide 382

1-[4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}1H-1,2,3-triazol-1-yl)butyl]-N-[(3- fluoropyridin-2-yl)methyl]-1H-1,2,3-triazole-4-carboxamide 383

1-[4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-[(6- methylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxamide 384

N-[(5-chloro-2-fluorophenyl)methyl]- 1-[4-(4-{2-[2-fluoro-5-(trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3- triazole-4-carboxamide 385

1-(4-{4-[2-(5-chloro-2- fluorophenyl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-{[3- (trifluoromethoxy)phenyl]methyl}-1H-1,2,3-triazole-4-carboxamide 386

1-(4-{4-[2-(5-chloro-2- fluorophenyl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}-1H-1,2,3-triazole-4-carboxamide 387

1-(4-{4-[2-(5-chloro-2- fluorophenyl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-[(3- fluoropyridin-2-yl)methyl]-1H-1,2,3-triazole-4-carboxamide 388

1-(4-{4-[2-(5-chloro-2- fluorophenyl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-[(6- methylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxamide 389

1-(3-fluoro-4-{4-[2-(3-fluoroazetidin-1-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-(pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide 390

1-(4-{4-[2-(3,3-difluoroazetidin-1-yl)acetamido]-1H-1,2,3-triazol-1-yl}- 3-fluorobutyl)-N-{[2-fluoro-5-(trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide 391

1-(4-{4-[2-(3,3-difluoroazetidin-1-yl)acetamido]-1H-1,2,3-triazol-1-yl}- 3-fluorobutyl)-N-{[3-(trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide 392

1-(4-{4-[2-(3,3-difluoroazetidin-1-yl)acetamido]-1H-1,2,3-triazol-1-yl}-3-fluorobutyl)-N-(pyridin-2-ylmethyl)- 1H-1,2,3-triazole-4-carboxamide393

1-(4-{4-[2-(3,3-difluoroazetidin-1-yl)acetamido]-1H-1,2,3-triazol-1-yl}-3-fluorobutyl)-N-[(6-methylpyridin-3- yl)methyl]-1H-1,2,3-triazole-4-carboxamide 394

1-[3-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl1-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide395

1-[3-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide396

1-[2-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-[(6- methylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxamide 397

1-(2-fluoro-4-(5-(2-(4-(3- (trifluoromethoxy)phenyl)pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2- yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide 398

1-[2-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N- (pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide 399

1-(3-fluoro-4-{4-[2-(pyridin-2- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4-carboxamide 400

1-(3-fluoro-4-{4-[2-(6-methylpyridin-3-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide401

1-(3-fluoro-4-{4-[2-(3-fluoroazetidin-1-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide402

1-(4-{4-[2-(3,3-difluoroazetidin-1-yl)acetamido]-1H-1,2,3-triazol-1-yl}- 3-fluorobutyl)-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide403

1-[2-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N- (pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide 404

1-[2-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)buty]-N-{[2- fluoro-5-(trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide 405

1-(2-fluoro-4-{4-[2-(6-methylpyridin-3-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-{[2-fluoro-5-(trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide 406

1-[2-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-[(3- fluoropyridin-2-yl)methyl]-1H-1,2,3-triazole-4-carboxamide 407

1-[2-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide408

1-[2-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-{[3- (trifluoromethoxy)phenyl]methyl}-1H-1,2,3-triazole-4-carboxamide 409

1-(3-fluoro-4-{4-[2-(3-fluoroazetidin-1-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-1,2,3-triazole-4- carboxamide 410

1-(4-{4-[2-(3,3-difluoroazetidin-1-yl)acetamido]-1H-1,2,3-triazol-1-yl}-3-fluorobutyl)-N-[(3-fluoropyridin-2- yl)methyl]-1H-1,2,3-triazole-4-carboxamide 411

1-[3-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide412

1-[3-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide413

1-[4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide414

1-[4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide415

1-(4-{4-[2-(5-chloro-2- fluorophenyl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-[(5-chloro-2- fluorophenyl)methyl]-1H-1,2,3-triazole-4-carboxamide 416

1-[2-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-{[3- (trifluoromethoxy)phenyl]methyl}-1H-1,2,3-triazole-4-carboxamide 417

1-[2-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-[(3- fluoropyridin-2-yl)methyl]-1H-1,2,3-triazole-4-carboxamide 418

1-[2-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide419

1-(2-fluoro-4-{4-[2-(pyridin-2- yl)acetamido]-1H-1,2,3-triazol-1-yl}butyl)-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}-1H-1,2,3-triazole-4-carboxamide 420

5-[3-fluoro-4-(4-{[(6-methylpyridin- 3-yl)methyl]carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N-{[3- (trifluoromethoxy)phenyl]methyl}-1,3,4-thiadiazole-2-carboxamide 421

1-{2-fluoro-4-[4-({[6- (trifluoromethyl)pyridin-3-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[2-fluoro-5-(trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide 422

1-{2-fluoro-4-[4-({[6- (trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[-fluoro-5-(trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide 423

1-{2-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide 424

1-{2-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-1,2,3- triazole-4-carboxamide 425

1-{2-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[6-(trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide 426

1-{2-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4- carboxamide 427

1-{2-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-[(3-fluoropyridin-2-yl)methyl]-1H-1,2,3-triazole-4- carboxamide 428

1-{2-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide 429

1-{2-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-[(3-fluoropyridin-2-yl)methyl]-1H-1,2,3-triazole-4- carboxamide 430

1-{2-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-[(6-methylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4- carboxamide 431

1-{2-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide 432

1-{2-fluoro-4-[4-({[4- (trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[-fluoro-5-(trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide 433

1-{2-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[3-(trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide 434

1-[2-fluoro-4-(4-{[(6-methylpyridin- 3-yl)methyl]carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N-{[3- (trifluoromethoxy)phenyl]methyl}-1H-1,2,3-triazole-4-carboxamide 435

1-{2-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-1,2,3- triazole-4-carboxamide 436

1-{2-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[6-(trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide 437

1-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-1,2,3- triazole-4-carboxamide 438

1-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[6-(trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide 439

1-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide 440

1-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-[(3-fluoropyridin-2-yl)methyl]-1H-1,2,3-triazole-4- carboxamide 441

1-{2-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[2-fluoro-5-(trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide 442

5-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-[(6-methylpyridin-3-yl)methyl]-1,3,4-thiadiazole-2- carboxamide 443

5-{3-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-[(6-methylpyridin-3-yl)methyl]-1,3,4-thiadiazole-2- carboxamide 444

1-{3-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-[(3-fluoropyridin-2-yl)methyl]-1H-1,2,3-triazole-4- carboxamide 445

5-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[3-(trifluoromethoxy)phenyl]methyl}- 1,3,4-thiadiazole-2-carboxamide 446

5-{3-fluoro-4-[4-({[4- (trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[3-(trifluoromethoxy)phenyl]methyl}- 1,3,4-thiadiazole-2-carboxamide 447

5-[3-fluoro-4-(4-{[(6-methylpyridin- 3-yl)methyl]carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}-1,3,4-thiadiazole-2-carboxamide 448

5-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[2-fluoro-5-(trifluoromethoxy)phenyl]methyl}- 1,3,4-thiadiazole-2-carboxamide 449

5-{3-fluoro-4-[4-({[4- (trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[2-fluoro-5-(trifluoromethoxy)phenyl]methyl}- 1,3,4-thiadiazole-2-carboxamide 450

N-benzyl-1-{2-fluoro-4-[4-({[4- (trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1H-1,2,3-triazole-4-carboxamide 451

5-{3-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-1,3,4- thiadiazole-2-carboxamide 452

1-{2-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-[(1S)-2-hydroxy-1-phenylethyl]-1H-1,2,3-triazole-4- carboxamide 453

1-{2-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-[(1R)-2-hydroxy-1-phenylethyl]-1H-1,2,3-triazole-4- carboxamide 454

1-[2-fluoro-4-(4-{[(2- fluorophenyl)methyl]carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4- carboxamide 455

1-{2-fluoro-4-[4-({[3- (trifluoromethyl)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide 456

1-(4-{4- [(cyclohexylmethyl)carbamoyl]-1H-1,2,3-triazol-1-yl}-2-fluorobutyl)-N- {[4-(trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4- carboxamide 457

1-(2-fluoro-4-{4-[(oxan-4- ylmethyl)carbamoyl]-1H-1,2,3-triazol-1-yl}butyl)-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4- carboxamide 458

1-[2-fluoro-4-(4-{[(1S)-1- phenylethyl]carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4- carboxamide 459

1-[2-fluoro-4-(4-{[(4- fluorophenyl)methyl]carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4-carboxamide 460

1-{4-[4-(benzylcarbamoyl)-1H-1,2,3- triazol-1-yl]-2-fluorobutyl}-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide461

1-{2-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-[(1R)-2-hydroxy-1-phenylethyl]-1H-1,2,3-triazole-4- carboxamide 462

1-{2-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-[(1S)-2-hydroxy-1-phenylethyl]-1H-1,2,3-triazole-4- carboxamide 463

5-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-1,3,4-thiadiazole-2- carboxamide 464

5-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-1,3,4-thiadiazole-2- carboxamide 465

5-{3-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-1,3,4-thiadiazole-2- carboxamide 466

1-[2-fluoro-4-(4-{[(3- fluorophenyl)methyl]carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4-carboxamide 467

1-[2-fluoro-4-(4-{[(1R)-2-hydroxy-1- phenylethyl]carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4-carboxamide 468

1-[2-fluoro-4-(4-{[(3- methoxyphenyl)methyl]carbamoyl}-1H-1,2,3-triazol-1-yl)butyl]-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide469

1-{2-fluoro-4-[4-({[4- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4- carboxamide 470

1-{2-fluoro-4-[4-({[4- (trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[4-(trifluoromethyl)pyridin-2-yl] methyl}-1H-1,2,3-triazole-4- carboxamide471

1-(4-{4- [(cyclopentylmethyl)carbamoyl]-1H-1,2,3-triazol-1-yl}-2-fluorobutyl)-N- {[4-(trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4- carboxamide 472

1-(2-fluoro-4-{4-[(oxan-2- ylmethyl)carbamoyl]-1H-1,2,3-triazol-1-yl}butyl)-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4-carboxamide 473

1-(2-fluoro-4-{4-[(oxan-3- ylmethyl)carbamoyl]-1H-1,2,3-triazol-1-yl}butyl)-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4-carboxamide 474

1-{2-fluoro-4-[4-({[6- (trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide475

1-{2-fluoro-4-[4-(methylcarbamoyl)- 1H-1,2,3-triazol-1-yl]butyl}-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide476

1-{2-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-3-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide477

1-{2-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[5-(trifluoromethyl)pyridin-3-yl]methyl}-1H-1,2,3- triazole-4-carboxamide 478

1-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[5-(trifluoromethyl)pyridin-3-yl]methyl}-1H-1,2,3- triazole-4-carboxamide 479

1-{2-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[5-(trifluoromethyl)pyridin-3-yl]methyl}-1H-1,2,3- triazole-4-carboxamide 480

5-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-3-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[3-(trifluoromethyl)phenyl]methyl}- 1,3,4-thiadiazole-2-carboxamide 481

5-[4-(4-{[(6-cyclopropylpyridin-3- yl)methyl]carbamoyl}-1H-1,2,3-triazol-1-yl)-3-fluorobutyl]-N-{[3- (trifluoromethyl)phenyl]methyl}-1,3,4-thiadiazole-2-carboxamide 482

5-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-3-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[3-(trifluoromethoxy)phenyl]methyl}- 1,3,4-thiadiazole-2-carboxamide 483

5-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[5-(trifluoromethyl)pyridin-3-yl]methyl}-1,3,4- thiadiazole-2-carboxamide 484

5-{3-fluoro-4-[4-({[3- (trifluoromethyl)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[5-(trifluoromethyl)pyridin-3-yl]methyl}-1,3,4- thiadiazole-2-carboxamide 485

5-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-3-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[4-(trifluoromethyl)pyridin-2-yl] methyl}-1,3,4-thiadiazole-2- carboxamide486

1-[3-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide487

1-[3-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-{[6-(trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide488

5-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-3-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl}- 1,3,4-thiadiazole-2-carboxamide489

5-{3-fluoro-4-[4-({[4- (trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl}- 1,3,4-thiadiazole-2-carboxamide490

5-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-3-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[6-(trifluoromethyl)pyridin-2-yl]methyl}- 1,3,4-thiadiazole-2-carboxamide491

5-{3-fluoro-4-[4-({[4- (trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[6-(trifluoromethyl)pyridin-2-yl]methyl}- 1,3,4-thiadiazole-2-carboxamide492

5-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[6-(trifluoromethyl)pyridin-2-yl]methyl}- 1,3,4-thiadiazole-2-carboxamide493

1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1,3,4-thiadiazol-2-yl)butyl]-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide494

1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1,3,4-thiadiazol-2-yl)butyl]-N-{[6-(trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide495

1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1,3,4-thiadiazol-2-yl)butyl]-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide496

1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1,3,4-thiadiazol-2-yl)butyl]-N-{[5-(trifluoromethyl)pyridin-3-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide497

1-(2-fluoro-4-(5-(2-(3- (trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-methyl- 1H-1,2,3-triazole-4-carboxamide498

1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1,3,4-thiadiazol-2-yl)butyl]-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide499

5-{3-fluoro-4-[4-({[4- (trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-(2,2,2-trifluoroethyl)-1,3,4-thiadiazole- 2-carboxamide 500

5-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-3-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-(2,2,2-trifluoroethyl)-1,3,4-thiadiazole- 2-carboxamide 501

5-{3-fluoro-4-[4-(methylcarbamoyl)- 1H-1,2,3-triazol-1-yl]butyl}-N-{[-(trifluoromethyl)pyridin-3-yl]methyl}- 1,3,4-thiadiazole-2-carboxamide502

5-(3-fluoro-4-{4-[(3,3,3- trifluoropropyl)carbamoyl]-1H-1,2,3-triazol-1-yl}butyl)-N-{[5- (trifluoromethyl)pyridin-3-yl]methyl}-1,3,4-thiadiazole-2-carboxamide 503

5-{3-fluoro-4-[4-({[4- (trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-methyl-1,3,4-thiadiazole-2-carboxamide 504

5-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-methyl-1,3,4-thiadiazole-2-carboxamide 505

N-(cyanomethyl)-1-[2-fluoro-4-(5-{2- [3-(trifluoromethoxy)phenyl]acetamido}-1,3,4-thiadiazol-2-yl)butyl]-1H-1,2,3- triazole-4-carboxamide 506

5-(3-fluoro-4-{4-[(2,2,2- trifluoroethyl)carbamoyl]-1H-1,2,3-triazol-1-yl}butyl)-N-{[5- (trifluoromethyl)pyridin-3-yl]methyl}-1,3,4-thiadiazole-2-carboxamide 507

5-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-3-yl]methyl}carbamoyl)-1H-1,2,3 -triazol-1-yl]butyl}-N-methyl-1,3,4-thiadiazole-2-carboxamide 508

5-{3-fluoro-4-[4-(methylcarbamoyl)- 1H-1,2,3-triazol-1-yl]butyl}-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}- 1,3,4-thiadiazole-2-carboxamide509

5-(3-fluoro-4-{4-[(2,2,2- trifluoroethyl)carbamoyl]-1H-1,2,3-triazol-1-yl}butyl)-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}-1,3,4-thiadiazole-2-carboxamide 510

5-(3-fluoro-4-{4-[(3,3,3- trifluoropropyl)carbamoyl]-1H-1,2,3-triazol-1-yl}butyl)-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}-1,3,4-thiadiazole-2-carboxamide 511

5-{3-fluoro-4-[4-({[4- (trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-(3,3,3-trifluoropropyl)-1,3,4-thiadiazole- 2-carboxamide 512

5-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-3-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-(3,3,3-trifluoropropyl)-1,3,4-thiadiazole- 2-carboxamide 513

1-(2-fluoro-4-{5-[2-(pyridin-2- yl)acetamido]-1,3,4-thiadiazol-2-yl}butyl)-N-{[3- (trifluoromethoxy)phenyl]methyl}-1H-1,2,3-triazole-4-carboxamide 514

1-(2-fluoro-4-{5-[2-(pyridin-2- yl)acetamido]-1,3,4-thiadiazol-2-yl}butyl)-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}-1H-1,2,3-triazole-4-carboxamide 515

N-(cyanomethyl)-5-{3-fluoro-4-[4- ({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1,3,4-thiadiazole-2-carboxamide 516

1-[2-fluoro-4-(5-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}-1,3,4-thiadiazol-2-yl)butyl]-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide517

1-[2-fluoro-4-(5-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}-1,3,4-thiadiazol-2-yl)butyl]-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide518

1-[2-fluoro-4-(5-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}-1,3,4-thiadiazol-2-yl)butyl]-N-methyl- 1H-1,2,3-triazole-4-carboxamide519

1-(2-fluoro-4-{5-[2-(pyridin-2- yl)acetamido]-1,3,4-thiadiazol-2-yl}butyl)-N-methyl-1H-1,2,3- triazole-4-carboxamide 520

5-{3-fluoro-4-[4-({[4- (trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}- 1,3,4-thiadiazole-2-carboxamide521

5-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1,3,4-thiadiazole-2-carboxamide 522

N-ethyl-5-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1,3,4-thiadiazole-2-carboxamide 523

5-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-(2-methoxyethyl)-1,3,4-thiadiazole-2-carboxamide 524

1-[3-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-methyl- 1H-1,2,3-triazole-4-carboxamide525

1-[3-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-methyl- 1H-1,2,3-triazole-4-carboxamide526

N-(propan-2-yl)-1-[4-(6-{2-[3- (trifluoromethoxy)phenyl]acetamido}pyridazin-3-yl)butyl]-1H-1,2,3- triazole-4-carboxamide 527

N-(cyanomethyl)-1-[4-(6-{2-[3- (trifluoromethoxy)phenyl]acetamido}pyridazin-3-yl)butyl]-1H-1,2,3- triazole-4-carboxamide 528

N-(2-hydroxyethyl)-1-[4-(6-{2-[3- (trifluoromethoxy)phenyl]acetamido}pyridazin-3-yl)butyl]-1H-1,2,3- triazole-4-carboxamide 529

N-(pyridin-2-ylmethyl)-1-[4-(6-{2-[3-(trifluoromethoxy)phenyl]acetamido} pyridazin-3-yl)butyl]-1H-1,2,3-triazole-4-carboxamide 530

1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1,3,4-thiadiazol-2-yl)butyl]-1H-1,2,3- triazole-4-carboxamide 531

N-ethyl-1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1,3,4-thiadiazol-2-yl)butyl]-1H-1,2,3- triazole-4-carboxamide 532

1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1,3,4-thiadiazol-2-yl)butyl]-N-(2- methoxyethyl)-1H-1,2,3-triazole-4-carboxamide 533

1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1,3,4-thiadiazol-2-yl)butyl]-N- (pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide 534

N-cyclopropyl-1-[2-fluoro-4-(5-{2-[3-(trifluoromethoxy)phenyl]acetamido}-1,3,4-thiadiazol-2-yl)butyl]-1H-1,2,3- triazole-4-carboxamide 535

N-(cyclopropylmethyl)-1-[2-fluoro-4- (5-{2-[3-(trifluoromethoxy)phenyl]acetamido}-1,3,4-thiadiazol-2-yl)butyl]-1H-1,2,3- triazole-4-carboxamide 536

1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1,3,4-thiadiazol-2-yl)butyl]-N-(2,2,2-trifluoroethyl)-1H-1,2,3-triazole-4- carboxamide 537

1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1,3,4-thiadiazol-2-yl)butyl]-N-[(3- fluoropyridin-2-yl)methyl]-1H-1,2,3-triazole-4-carboxamide 538

1-[2-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-methyl- 1H-1,2,3-triazole-4-carboxamide539

1-[2-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}-1H-1,2,3-triazol-1-yl)butyl]-N-methyl- 1H-1,2,3-triazole-4-carboxamide540

1-(2-fluoro-4-(5-(2-(pyridin-2- yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-((4- (trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide 541

N-methyl-1-(4-{6-[2-(pyridin-3- yl)acetamido]pyridazin-3-yl}butyl)-1H-1,2,3-triazole-4-carboxamide 542

1-(4-{6-[2-(3- bromophenyl)acetamido]pyridazin-3-yl}butyl)-N-methyl-1H-1,2,3-triazole- 4-carboxamide 543

1-(4-{6-[2-(3- methanesulfonylphenyl)acetamido]pyridazin-3-yl}butyl)-N-methyl-1H- 1,2,3-triazole-4-carboxamide 544

1-(4-{6-[2-(6-chloropyridin-3- yl)acetamido]pyridazin-3-yl}butyl)-N-methyl-1H-1,2,3-triazole-4- carboxamide 545

N-methyl-1-[4-(6-{2-[3-(pyridin-2- yl)phenyl]acetamido}pyridazin-3-yl)butyl]-1H-1,2,3-triazole-4- carboxamide 546

1-(4-{6-[2-(5-bromopyridin-3- yl)acetamido]pyridazin-3-yl}butyl)-N-methyl-1H-1,2,3-triazole-4- carboxamide 547

N-methyl-1-(4-{6-[2-(oxan-4- yl)acetamido]pyridazin-3-yl}butyl)-1H-1,2,3-triazole-4-carboxamide 548

1-{4-[6-(2- cyclopentylacetamido)pyridazin-3-yl]butyl}-N-methyl-1H-1,2,3-triazole- 4-carboxamide 549

N-(2-hydroxy-2-methylpropyl)-1-[4- (6-{2-[3-(trifluoromethoxy)phenyl]acetamido} pyridazin-3-yl)butyl]-1H-1,2,3-triazole-4-carboxamide 550

N-(oxetan-3-ylmethyl)-1-[4-(6-{2-[3- (trifluoromethoxy)phenyl]acetamido}pyridazin-3-yl)butyl]-1H-1,2,3- triazole-4-carboxamide 551

N-(2-methoxyethyl)-1-[4-(6-{2-[3- (trifluoromethoxy)phenyl]acetamido}pyridazin-3-yl)butyl]-1H-1,2,3- triazole-4-carboxamide 552

N-[3-hydroxy-2- (hydroxymethyl)propyl]-1-[4-(6-{2-[3-(trifluoromethoxy)phenyl]acetamido} pyridazin-3-yl)butyl]-1H-1,2,3-triazole-4-carboxamide 553

1-(4-{5-[2-(pyridin-2-yl)acetamido]- 1,3,4-thiadiazol-2-yl}butyl)-N-{[3-(trifluoromethoxy)phenyl]methyl}-1H- 1,2,3-triazole-4-carboxamide 554

N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}-1-(4-{5-[2-(pyridin-2-yl)acetamido]-1,3,4-thiadiazol-2-yl}butyl)-1H-1,2,3- triazole-4-carboxamide 555

5-{3-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-methyl-1,3,4-thiadiazole-2-carboxamide 556

5-{4-[4-(benzylcarbamoyl)-1H-1,2,3-triazol-1-yl]-3-fluorobutyl}-N-methyl- 1,3,4-thiadiazole-2-carboxamide557

5-(3-fluoro-4-{4-[(pyridin-2- ylmethyl)carbamoyl]-1H-1,2,3-triazol-1-yl}butyl)-N-methyl-1,3,4- thiadiazole-2-carboxamide 558

1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1,3,4-thiadiazol-2-yl)butyl]-N-(oxetan- 3-ylmethyl)-1H-1,2,3-triazole-4-carboxamide 559

1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}-1,3,4-thiadiazol-2-yl)butyl]-N-[(6- methylpyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carboxamide 560

N-(3-hydroxy-2,2-dimethylpropyl)-1- [4-(6-{2-[3-(trifluoromethoxy)phenyl]acetamido} pyridazin-3-yl)butyl]-1H-1,2,3-triazole-4-carboxamide 561

5-{3-fluoro-4-[4-(methylcarbamoyl)- 1H-1,2,3-triazol-1-yl]butyl}-N-{[3-(trifluoromethoxy)phenyl]methyl}- 1,3,4-thiadiazole-2-carboxamide 562

5-{3-fluoro-4-[4-(methylcarbamoyl)- 1H-1,2,3-triazol-1-yl]butyl}-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}-1,3,4-thiadiazole-2-carboxamide 563

N-benzyl-5-{3-fluoro-4-[4- (methylcarbamoyl)-1H-1,2,3-triazol-1-yl]butyl}-1,3,4-thiadiazole-2- carboxamide 564

1-(4-{5-[2-(5-chloro-3-fluoropyridin-2-yl)acetamido]-1,3,4-thiadiazol-2- yl}-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide 565

N-methyl-1-(4-(6-(2-(3-(pyrrolidin-1- yl)phenyl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4- carboxamide 566

1-(4-(5-acetamido-1,3,4-thiadiazo1-2- yl)-2-fluorobutyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3- triazole-4-carboxamide 567

1-(4-(5-acetamido-1,3,4-thiadiazol-2- yl)-2-fluorobutyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)- 1H-1,2,3-triazole-4-carboxamide568

1-(4-(5-(cyclopropanecarboxamido)-1,3,4-thiadiazol-2-yl)-2-fluorobutyl)-N-(3-(trifluoromethoxy)benzyl)-1H- 1,2,3-triazole-4-carboxamide 569

1-(4-(5-(cyclopropanecarboxamido)-1,3,4-thiadiazol-2-yl)-2-fluorobutyl)- N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4- carboxamide 570

5-(3-fluoro-4-(4-(methylcarbamoyl)- 1H-1,2,3-triazol-1-yl)butyl)-N-(pyridin-2-ylmethyl)-1,3,4- thiadiazole-2-carboxamide 571

1-(2-fluoro-4-(5-(2-(pyridin-2- yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-((5- (trifluoromethyl)pyridin-3-yl)methyl)-1H-1,2,3-triazole-4-carboxamide 572

N-methyl-5-(4-(6-(2-(3- (trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1,3,4- thiadiazole-2-carboxamide 573

1-(2-fluoro-4-(5-(2-(thiazol-2- yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-(2-fluoro-5- (trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide 574

1-(2-fluoro-4-(5-(tetrahydro-2H-pyran-2-carboxamido)-1,3,4-thiadiazol-2- yl)butyl)-N-(2-fluoro-5-(trifluoromethoxy)benzyl)-1H-1,2,3- triazole-4-carboxamide 575

1-(4-(5-(2-(1H-pyrazol-5- yl)acetamido)-1,3,4-thiadiazol-2-yl)-2-fluorobutyl)-N-(2-fluoro-5- (trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide 576

1-(2-fluoro-4-(5-(2-(1-methyl-1H- imidazol-4-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-(2-fluoro-5-(trifluoromethoxy)benzyl)-1H-1,2,3- triazole-4-carboxamide 577

N-(5-(3-fluoro-4-(4-((2-fluoro-5- (trifluoromethoxy)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1,3,4- thiadiazol-2-yl)nicotinamide 578

1-(2-fluoro-4-(5-(2-(pyridin-3- yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-methyl-1H-1,2,3-triazole- 4-carboxamide 579

N-methyl-1-(4-(6-(2-(pyrazin-2- yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide 580

1-(4-(5-(2-(4-cyclopropylpyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)- 2-fluorobutyl)-N-((5-(trifluoromethyl)pyridin-3-yl)methyl)- 1H-1,2,3-triazole-4-carboxamide581

1-(4-(6-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-N-(oxetan-3-yl)- 1H-1,2,3-triazole-4-carboxamide582

1-(4-(6-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-N-(oxetan-2- ylmethyl)-1H-1,2,3-triazole-4-carboxamide 583

N-cyclopropyl-1-(4-(6-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamido) pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide 584

1-(4-(6-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-N-(2- methoxyethyl)-1H-1,2,3-triazole-4-carboxamide 585

1-(4-(6-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-N-(pyridin-2- ylmethyl)-1H-1,2,3-triazole-4-carboxamide 586

1-(4-(6-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-N-(pyridin-3- ylmethyl)-1H-1,2,3-triazole-4-carboxamide 587

1-(4-(6-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-N-(pyridin-4- ylmethyl)-1H-1,2,3-triazole-4-carboxamide 588

N-(2-fluoro-5- (trifluoromethoxy)benzyl)-1-(4-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3- yl)butyl)-1H-1,2,3-triazole-4-carboxamide 589

N-(2-fluoro-5- (trifluoromethoxy)benzyl)-1-(4-(6-(2-(pyridin-3-yl)acetamido)pyridazin-3- yl)butyl)-1H-1,2,3-triazole-4-carboxamide 590

N-(2-fluoro-5- (trifluoromethoxy)benzyl)-1-(4-(6-(2-(pyridin-4-yl)acetamido)pyridazin-3- yl)butyl)-1H-1,2,3-triazole-4-carboxamide 591

1-4-(6- (cyclopropanecarboxamido)pyridazin- 3-yl)butyl)-N-(2-fluoro-5-(trifluoromethoxy)benzyl)-1H-1,2,3- triazole-4-carboxamide 592

1-(2-fluoro-4-(5-(2-(6-fluoropyridin-2-yl)acetamido)-1,3,4-thiadiazol-2- yl)butyl)-N-(2-fluoro-5-(trifluoromethoxy)benzyl)-1H-1,2,3- triazole-4-carboxamide 593

1-(2-fluoro-4-(5-(2-(thiazol-5- yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-(2-fluoro-5- (trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide 594

N-(5-(3-fluoro-4-(4-((2-fluoro-5- (trifluoromethoxy)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1,3,4- thiadiazol-2-yl)isonicotinamide 595

N-(5-(3-fluoro-4-(4-((2-fluoro-5- (trifluoromethoxy)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1,3,4- thiadiazol-2-yl)picolinamide 596

1-(4-(6-(2-(3- (trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3- triazole-4-carboxamide 597

5-(4-(6-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-N-(2- hydroxyethyl)-1,3,4-thiadiazole-2-carboxamide 598

5-(4-(6-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1,3,4- thiadiazole-2-carboxamide 599

5-(4-(6-acetamidopyridazin-3-yl) butyl)-N-(3-(trifluoromethoxy)benzyl)-1,3,4-thiadiazole-2- carboxamide 600

5-(4-(6-acetamidopyridazin-3-yl) butyl)-N-(2-fluoro-5-(trifluoromethoxy)benzyl)-1,3,4- thiadiazole-2-carboxamide 601

5-(4-(6-acetamidopyridazin-3-yl) butyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1,3,4- thiadiazole-2-carboxamide 602

5-(4-(6-acetamidopyridazin-3-yl) butyl)-N-((5-(trifluoromethyl)pyridin-3-yl)methyl)-1,3,4- thiadiazole-2-carboxamide 603

N-methyl-5-(4-(4-(((4- (trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)-1H-1,2,3- triazol-1-yl)butyl)-1,3,4-thiadiazole-2-carboxamide 604

N-methyl-1-(4-(6-(2-(1-(3- (trifluoromethoxy)phenyl)-1H-imidazol-4-yl)acetamido)pyridazin- 3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide 605

N-methyl-1-(4-(6-(2-(4-(2- (trifluoromethyl)phenyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide 606

1-(4-(6-(2-(4-(4-fluoro-2- (trifluoromethyl)phenyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)- N-methyl-1H-1,2,3-triazole-4-carboxamide 607

1-(4-(6-(2-(4-(2-fluoro-3- (trifluoromethoxy)phenyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)- N-methyl-1H-1,2,3-triazole-4-carboxamide 608

1-(4-(6-(2-(4-(3-chloro-2- (trifluoromethoxy)phenyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)- N-methyl-1H-1,2,3-triazole-4-carboxamide 609

1-(4-(6-(2-(4-(5-fluoro-2- methylphenyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)- N-methyl-1H-1,2,3-triazole-4-carboxamide

Table 2 below reports the calculated observed molecular weight of eachExample, as well as the method by which each compound may be made byreference to each Example whose synthesis is substantially similar thatone skilled in the art could produce the compound using, if necessary,variations know in the art.

TABLE 2 Observed Molecular Weight and Synthesis for Examples Ex. Calc.Obs Method No. Mass Mass as in Ex. 10 511 512 1 11 523 524 1 12 553 5541 13 489 490 1 14 512 513 1 15 475 476 1 16 559 560 1 17 513 514 1 18587 588 1 19 560 561 1 20 643 644 1 21 589 590 1 22 619 620 1 23 589 5901 24 435 435 5 25 516 517 6 26 500 501 6 27 501 502 6 28 486 487 6 29502 503 6 30 487 488 6 31 536 537 6 32 571 572 6 33 550 551 6 34 552 5536 34 577 578 6 36 570 571 6 37 524 525 6 38 427 428 7 39 559 560 7 40476 477 7 41 429 430 7 42 441 442 7 43 511 512 7 44 525 526 7 45 513 5147 46 643 644 7 47 560 561 7 48 541 542 7 49 566 567 7 50 539 540 7 51525 526 7 52 443 444 7 53 606 607 8 54 510 511 9 55 522 523 9 56 538 5399 57 508 509 9 58 494 495 9 59 523 524 7 60 574 575 7 61 574 575 7 62491 492 7 63 454 455 7 64 505 506 7 65 560 561.5 7 66 477 478 7 67 491491 7 68 440 441 7 69 440 441 7 70 454 455 7 71 460 461 80 72 557 558 8073 638 639 7 74 569 570 7 75 628 629 7 76 628 629 7 77 628 629 7 78 628629 7 79 621 622 80 80 611 612 80 81 611 612 80 82 611 612 80 83 611 61280 84 519 520 80 85 505 506 80 86 521 522 80 87 507 508 80 88 451 452 8089 491 492 80 90 533 534 80 91 507 508 80 92 521 522 80 93 505 506 80 94550 551 80 95 466 467 80 96 527 528 80 97 595 596 80 98 541 542 80 99541 542 80 100 557 558 80 101 557 558 80 102 547 548 80 103 547 548 80104 505 506 80 105 567 568 80 106 583 584 80 107 579 580 80 108 557 55880 109 625 626 80 110 656 657 80 111 561 562 80 112 545 546 80 113 557558 80 114 535 536 80 115 562 563 80 116 562 563 80 117 550 551 80 118550 551 80 119 534 535 80 120 534 535 80 121 534 535 80 122 611 612 80123 557 558 80 124 596 597 80 125 601 602 80 126 544 545 80 127 544 54580 128 539 540 80 129 557 558 475 130 575 576 475 131 559 560 475 132593 594 80 133 567 568 80 134 557 558 475 135 568 569 80 136 599 600 80137 599 600 80 138 572 573 80 139 572 573 80 140 596 597 80 141 596 59780 142 596 597 80 143 596 597 80 144 596 597 80 145 614 615 475 146 634635 80 147 601 602 475 148 601 602 475 149 469 470 475 150 502 503 475151 469 470 475 152 586 587 475 153 502 503 475 154 483 484 475 155 591592 475 156 614 615 475 157 477 478 157 158 596 597 80 159 560 561 475160 495 496 157 161 393 394 157 162 484 485 475 163 401 402 475 164 441442 475 165 400 401 475 166 529 530 475 167 394 395 157 168 527 528 475169 554 555 157 170 451 452 475 171 451 452 475 172 522 523 157 173 467468 157 174 477 478 157 175 462 463 157 176 503 504 157 177 488 489 157178 478 479 157 179 407 408 157 180 445 446 157 181 466 467 475 182 425426 475 183 478 479 475 184 469 470 475 185 458 459 475 186 469 470 475187 415 416 475 188 554 555 188 189 486 487 508 190 434 435 192 191 428429 192 192 554 555 192 193 501 502 250 194 501 502 250 195 578 579 195196 524 525 540 197 596 597 250 198 596 597 250 199 475 476 192 200 472473/475 192 201 563 564 250 202 500 501 192 203 539 540 157 204 596 597540 205 626 627 540 206 626 627 540 207 554 555 192 208 478 479 192 209500 501 540 210 462 463 192 211 557 558 211 212 574 575 192 213 576 577192 214 414 415 192 215 476 477 192 216 571 572 229 217 477 478 192 218596 597 540 219 626 627 540 220 486 487 508 + separation 221 486 487508 + separation 222 626 627 540 223 626 627 540 224 478 479 157 225 492493 192 226 486 487 540 227 575 576 211 228 561 562 228 229 479 480 229230 645 646 157 231 577 578 157 232 561 562 228 233 464 465 233 234 563564 508 235 563 564 508 236 480 481 259 237 436 437 192 238 563 564 250239 501 502 250 240 501 502 250 241 593 594 259 242 572 573 242 243 401402 243 244 411 412 259 245 518 519 259 246 584 585 157 247 589 612 (M +211 Na+) 248 480 481 259 249 575 576 211 250 563 564 250 251 482 483 251252 518 519 272 253 496 497 253 254 412 413 259 255 572 573 242 256 412413 259 257 572 573 242 258 490 491 258 259 480 481 259 260 480 481 259261 500 501 261 262 510 511 262 263 520 521 268 264 494 495 268 265 502503 540 266 524 525 262 267 502 503 267 268 494 495 268 269 580 581 269270 561 562 270 271 512 513 271 272 518 519 272 273 411 412 259 274 478479 274 275 452 453 275 276 506 507 297 277 451 452 297 278 423 424 297279 543 544 297 280 465 466 297 281 428 429 297 282 456 457 297 283 470471 297 284 465 466 297 285 465 466 297 286 548 549 297 287 414 415 297288 442 443 297 289 456 457 297 290 451 452 297 291 451 452 297 292 534535 297 293 543 544 297 294 543 544 297 295 534 535 297 296 548 549 297297 460 461 297 298 460 461 297 299 557 558 297 300 437 438 297 301 506507 297 302 423 424 297 303 423 424 297 304 414 415 297 305 428 429 297306 474 475 297 307 543 544 297 308 423 424 297 309 451 452 297 310 465466 297 311 465 466 297 312 479 480 297 313 557 558 297 314 474 475 297315 474 475 297 316 488 489 297 317 465 466 297 318 479 480 297 319 437438 297 320 460 461 297 321 460 461 297 322 474 475 297 323 474 475 332324 456 457 332 325 488 489 332 326 502 503 332 327 561 562 347 328 575576 347 329 539 540 332 330 557 558 332 331 571 572 332 332 585 586 332333 644 645 297 334 594 595 297 335 575 576 297 336 525 526 297 337 561562 297 338 511 512 297 339 644 645 347 340 662 663 347 341 579 580 347342 575 576 347 343 593 594 347 344 492 493 347 345 510 511 347 346 506507 347 347 561 562 347 348 470 471 332 349 507 508 332 350 557 558 332351 488 489 332 352 525 526 332 353 575 576 332 354 502 503 332 355 539540 332 356 589 590 332 357 506 507 332 358 516 517 332 359 553 554 332360 603 604 332 361 520 521 332 362 478 479 347 363 579 580 347 364 492493 347 365 496 497 347 366 511 512 347 367 561 562 347 368 593 594 475369 579 580 475 370 593 594 475 371 557 558 372 372 575 576 372 373 579580 347 374 488 489 372 375 579 580 347 376 593 594 347 377 680 681 347378 597 598 347 379 662 663 347 380 644 645 297 381 662 663 297 382 579580 297 383 575 576 297 384 612 613 297 385 594 595 297 386 612 613 297387 529 530 297 388 525 526 297 389 474 475 372 390 593 594 372 391 575576 372 392 492 493 372 393 506 507 372 394 629 630 347 395 647 648 347396 575 576 347 397 578 579 t397 398 579 580 347 399 546 547 347 400 560561 347 401 542 543 372 402 560 561 372 403 561 562 372 404 680 681 347405 593 594 347 406 579 580 347 407 629 630 347 408 644 645 347 409 492493 372 410 510 511 372 411 629 630 347 412 647 648 347 413 629 630 297414 611 612 297 415 562 563 297 416 662 663 347 417 597 598 347 418 647648 347 419 579 580 347 420 592 593 508 421 647 648 475 422 647 648 475423 647 648 475 424 647 648 475 425 647 648 475 426 647 648 475 427 597598 475 428 629 630 475 429 579 580 475 430 575 576 431 629 630 475 432647 648 475 433 629 630 475 434 575 576 475 435 629 630 475 436 629 630475 437 629 630 475 438 629 630 475 439 629 630 475 440 579 580 475 441647 648 475 442 592 593 508 443 610 611 508 444 597 598 475 445 646 647508 446 646 647 508 447 610 611 508 448 664 665 508 449 664 665 508 450545 546 475 451 664 665 508 452 608 609 475 453 608 609 475 454 563 564475 455 613 614 475 456 551 552 475 457 553 554 475 458 559 560 475 459563 564 475 460 545 546 475 461 590 591 475 462 590 591 475 463 646 647508 464 646 647 508 465 664 665 508 466 563 564 475 467 575 576 475 468575 576 475 469 629 630 475 470 614 615 475 471 537 538 475 472 553 554475 473 553 554 475 474 614 615 475 475 469 470 475 476 614 615 475 477629 630 475 478 629 630 475 479 647 648 475 480 630 631 508 481 602 603508 482 646 647 508 483 646 647 508 484 630 631 508 485 631 632 508 486629 630 347 487 629 630 347 488 631 632 508 489 631 632 508 490 631 632508 491 631 632 508 492 631 632 508 493 646 647 540 494 646 647 540 495646 647 540 496 646 647 540 497 501 502 540 498 646 647 540 499 554 555508 500 554 555 508 501 486 487 508 502 568 569 508 503 486 487 508 504501 502 508 505 526 527 508 506 554 555 508 507 486 487 508 508 486 487508 509 554 555 508 510 568 569 508 511 568 569 508 512 568 569 508 513578 579 540 514 596 597 540 515 526 527 540 516 664 665 540 517 664 665540 518 519 520 540 519 418 419 540 520 631 632 508 521 487 488 508 522515 516 508 523 545 546 508 524 484 485 347 525 502 503 347 526 505 506157 527 502 503 157 528 507 508 157 529 554 555 157 530 487 488 540 531515 516 540 532 545 546 540 533 578 579 540 534 527 528 540 535 541 542540 536 569 570 540 537 596 597 540 538 484 485 347 539 502 503 347 540563 564 540 541 394 395 192 542 471 472 192 543 471 472 192 544 428 429192 545 470 471 192 546 472 473 192 547 401 402 192 548 385 386 192 549535 536 157 550 533 534 157 551 521 522 157 552 551 552 157 553 560 561540 554 578 579 540 555 519 520 508 556 417 418 508 557 418 419 508 558557 558 540 559 592 593 540 560 549 550 157 561 501 502 508 562 519 520508 563 417 418 508 564 470 471 540 565 462 463 192 566 501 502 540 567486 487 540 568 527 528 540 569 512 513 540 570 418 419 508 571 563 564540 572 494 495 6 573 602 603 540 574 589 590 540 575 585 586 540 576599 600 540 577 582 583 540 578 418 419 540 579 395 396 192 580 603 604540 581 537 538 157 582 551 552 157 583 521 522 157 584 539 540 157 585572 573.1907 157 586 572 573 157 587 572 573 157 588 572 573 192 589 572573 192 590 572 573 192 591 521 522 192 592 614 615 540 593 602 603 540594 582 583 540 595 582 583 540 596 463 464 157 597 542 543 6 598 512513 6 599 494 495 229 600 512 513 229 601 479 480 229 602 479 480 229603 468 469 7 604 543 544 192 605 538 539 605 606 556 557 605 607 572573 605 608 588 589 605 609 502 503 605

PROPHETIC EXAMPLES

The prophetic examples shown below further illustrate the scope of thisdisclosure. Non-limiting prophetic examples include the followingcompounds and pharmaceutically acceptable salts thereof:

Example 610:(R)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)-6-methylpyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

Example 611:(R)-1-(4-(6-(2-(4-cyclopropyl-6-methylpyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

It is believed that a person of skill in the art would know how tosynthesize the claimed compounds based, in part, on the provided Schemes6 and 7.

Biological Activity Assays

The following are assays that may be used to evaluate the biologicalefficacy of compounds of Formula (I).

GLS1 Enzymatic Activity Assay

The inhibition of purified recombinant human GAC by varyingconcentrations of inhibitors is assessed via a dual-coupled enzymaticassay. The glutamate produced by the glutaminase reaction is used byglutamate oxidase to produce α-ketoglutarate, ammonia, and hydrogenperoxide, with this hydrogen peroxide subsequently being used byhorseradish peroxidase to produce resorufin in the presence of AmplexUltraRed. The assay buffer consisted of 50 mM Hepes (pH 7.4), 0.25 mMEDTA and 0.1 mM Triton X-100. GAC was incubated with potassium phosphate(10 minutes at room temperature) prior to incubation with inhibitor (10minutes at room temperature). The final reaction conditions were asfollows: 2 nM GAC, 50 mM potassium phosphate, 100 mU/mL glutamateoxidase (Sigma), 1 mM glutamine (Sigma), 100 mU/mL horseradishperoxidase (Sigma), 75 μM Amplex UltraRed (Life Technologies), and 1%(v/v) DMSO. The production of resorufin was monitored on a Perkin ElmerEnvision plate reader (excitation 530 nm, emission 590 nm) either in akinetics or endpoint mode (at 20 minutes). IC50 values were calculatedusing a four-parameter logistic curve fit.

Proliferation Assay

A549 cells were routinely maintained in RPMI 1640 media (Gibco catalognumber 11875-093) supplemented with 10% dialyzed fetal bovine serumusing a humidified incubator (37° C., 5% CO2 and ambient O2). Inpreparation for the viability assay, cells were inoculated into 384-wellblack CulturPlates (Perkin Elmer) at a density of 1000 cells/well in avolume of 40 uL. Following a 24-hour incubation at 37° C., 5% CO2 andambient O2, cells were treated with compound (10 uL) in a final DMSOconcentration of 0.5% (v/v). The microplates were then incubated for 72hours (37° C., 5% CO2 and ambient O2). Cell Titer Fluor (Promega) wassubsequently added (10 uL of 6× reagent) and mixed for 15 minutes atroom temperature. The plates were then incubated for 30 minutes (37° C.,5% CO2 and ambient O2) and fluorescence was subsequently read on thePerkin Elmer Envision plate reader. IC50 values were calculated using afour-parameter logistic curve fit.

Non-limiting examples include the following compounds andpharmaceutically acceptable salts thereof. Table 3 below reports theIC₅₀ against GLS1 and the EC₅₀ against A549 cell proliferation, both innanomolar, and both wherein A<100 nM, B=100-500 nM, C>500-5000 nM, andD>5000 nM. “ND” indicates no data. Compounds disclosed herein and notyet tested are expected to demonstrate activity in these assays as well.

TABLE 3 Biological Data Ex. GLS1 A549 No. IC₅₀ EC₅₀ 1 A A 2 A A 3 B B 4B B 5 A A 6 A A 7 B B 8 B N.D. 9 C N.D. 10 B N.D. 11 A B 12 A A 13 A C14 C N.D. 15 A B 16 A A 17 B B 18 B B 19 A A 20 A A 21 A B 22 A B 23 A B24 A A 25 A B 26 A A 27 A A 28 A B 29 A A 30 A A 31 A A 32 A A 33 A A 34A B 34 B B 36 A A 37 A A 38 C N.D. 39 N.D. B 40 B N.D. 41 C C 42 N.D.N.D. 43 N.D. B 44 N.D. B 45 B C 46 A A 47 A B 48 C C 49 C D 50 B C 51 BC 52 C D 53 C N.D. 54 B BN.D. 55 B C 56 A A 57 C N.D. 58 C N.D. 59 B C60 A A 61 A A 62 B C 63 B C 64 A C 65 A B 66 C N.D. 67 B N.D. 68 C N.D.69 C N.D. 70 C N.D. 71 C N.D. 72 A A 73 A A 74 B N.D. 75 A A 76 A A 77 AA 78 A A 79 A A 80 A A 81 A A 82 A A 83 A A 84 B B 85 C C 86 C D 87 C D88 C C 89 C C 90 B B 91 C D 92 C C 93 B C 94 B B 95 B B 96 B B 97 A A 98C C 99 C C 100 C D 101 C C 102 C C 103 B C 104 C C 105 A A 106 A A 107 AA 108 A B 109 A B 110 A A 111 A A 112 B B 113 A C 114 C C 115 C C 116 AB 117 B B 118 B B 119 B B 120 B C 121 B B 122 A A 123 A B 124 A A 125 AB 126 B B 127 B C 128 A A 129 A A 130 B B 131 B B 132 A A 133 A A 134 AA 135 A A 136 A A 137 A A 138 B B 139 B B 140 A A 141 A A 142 A A 143 AA 144 A A 145 A A 146 A A 147 A A 148 A A 149 B C 150 B B 151 B C 152 AA 153 A B 154 C C 155 A C 156 A A 157 A B 158 A A 159 A B 160 A A 161 AA 162 B B 163 C C 164 A B 165 B C 166 A B 167 A B 168 A B 169 A A 170 BC 171 B C 172 A A 173 B B 174 A B 175 A B 176 A B 177 A B 178 A B 179 AC 180 A B 181 B C 182 B D 183 B D 184 C D 185 B C 186 B C 187 B D 188 AA 189 C D 190 A B 191 A B 192 A A 193 A C 194 A A 195 A A 196 C C 197 AA 198 A A 199 A B 200 A B 201 A B 202 A B 203 A A 204 A A 205 A A 206 AA 207 A A 208 A B 209 B B 210 A B 211 A A 212 A A 213 A A 214 B D 215 BC 216 A A 217 A B 218 A A 219 A A 220 B C 221 B B 222 A A 223 A A 224 BB 225 A B 226 A A 227 A A 228 A A 229 A A 230 A A 231 A A 232 A A 233 AA 234 A B 235 A B 236 A A 237 A B 238 A B 239 A B 240 A A 241 A A 242 AA 243 B B 244 A A 245 A A 246 A A 247 A A 248 A A 249 A A 250 A A 251 AA 252 A A 253 A A 254 A B 255 A A 256 A B 257 A A 258 A A 259 A A 260 AA 261 A A 262 A A 263 A A 264 A A 265 A A 266 A A 267 A A 268 A A 269 AA 270 A A 271 A A 272 A A 273 A A 274 A A 275 A A 276 B B 277 B C 278 CN.D. 279 A B 280 B C 281 C N.D. 282 C N.D. 283 C N.D. 284 B C 285 C C286 A B 287 C N.D. 288 B C 289 C N.D. 290 C N.D. 291 C N.D. 292 B C 293A B 294 A B 295 A A 296 A A 297 C N.D. 298 C N.D. 299 A A 300 C D 301 BC 302 C N.D. 303 C N.D. 304 C N.D. 305 C C 306 B C 307 A B 308 C N.D.309 B B 310 A B 311 B C 312 B C 313 A A 314 B C 315 B C 316 A C 317 B B318 A A 319 C D 320 B C 321 C C 322 B C 323 C N.D. 324 C N.D. 325 C N.D.326 C N.D. 327 A A 328 A A 329 B C 330 A B 331 A B 332 A B 333 C N.D.334 A A 335 A A 336 A B 337 A A 338 A B 339 A A 340 A A 341 A B 342 A A343 A A 344 B D 345 B D 346 A C 347 A A 348 C N.D. 349 B N.D. 350 B B351 C N.D. 352 B C 353 A B 354 C N.D. 355 B B 356 A A 357 C N.D. 358 CN.D. 359 B B 360 A A 361 C N.D. 362 C N.D. 363 A A 364 B C 365 C N.D.366 B C 367 A B 368 A A 369 A A 370 A A 371 A B 372 A B 373 A A 374 BN.D. 375 A A 376 A A 377 A A 378 A A 379 A A 380 A A 381 A A 382 A B 383A A 384 A A 385 A A 386 A A 387 B C 388 A B 389 C D 390 A A 391 A B 392C D 393 C C 394 A A 395 A A 396 A A 397 A A 398 A A 399 A B 400 A B 401B C 402 B C 403 A A 404 A A 405 A A 406 A A 407 A A 408 A A 409 C D 410C C 411 A A 412 A A 413 A A 414 A A 415 A A 416 A A 417 A A 418 A A 419A A 420 A B 421 A A 422 A A 423 A A 424 A A 425 A A 426 A A 427 A A 428A A 429 A B 430 A A 431 A A 432 A A 433 A A 434 A A 435 A A 436 A A 437A A 438 A A 439 A A 440 A B 441 A A 442 A A 443 A A 444 A A 445 A A 446A A 447 A A 448 A A 449 A A 450 A B 451 A A 452 A B 453 A B 454 A B 455A A 456 A A 457 C C 458 B B 459 A B 460 B B 461 B C 462 A B 463 A A 464A A 465 A A 466 A A 467 B B 468 A A 469 A A 470 A A 471 A B 472 B B 473B B 474 A A 475 B B 476 A A 477 A A 478 A A 479 A A 480 A A 481 A A 482A A 483 A A 484 A A 485 A A 486 A A 487 A A 488 A A 489 A A 490 A A 491A A 492 A B 493 A A 494 A A 495 A A 496 A A 497 A B 498 A A 499 B B 500B B 501 B B 502 B B 503 B C 504 A B 505 A B 506 B B 507 B B 508 B B 509B B 510 B C 511 B C 512 B B 513 A A 514 A A 515 A B 516 A A 517 A A 518A A 519 B C 520 A A 521 B B 522 A B 523 B C 524 A B 525 A B 526 B C 527A A 528 A C 529 A A 530 A C 531 A B 532 A B 533 A A 534 A B 535 A B 536A B 537 A B 538 A B 539 A B 540 A A 541 A C 542 A B 543 A C 544 A B 545A B 546 A B 547 B C 548 B C 549 B C 550 A B 551 A B 552 C D 553 A A 554A A 555 A B 556 B C 557 C C 558 A C 559 A B 560 A B 561 A B 562 A B 563C C 564 A C 565 A B 566 A B 567 A B 568 A B 569 A B 570 B C 571 A A 572A B 573 A A 574 A A 575 A B 576 A A 577 A C 578 A C 579 B C 580 A A 581A B 582 A B 583 A A 584 A B 585 A A 586 A A 587 A A 588 A A 589 A A 590A A 591 A B 592 A A 593 A A 594 A C 595 A A 596 A B 597 A B 598 A A 599A A 600 A A 601 A A 602 A A 603 C D 604 A A 605 A A 606 A A 607 A A 608A A 609 A A

OTHER EMBODIMENTS

The detailed description set-forth above is provided to aid thoseskilled in the art in practicing the present disclosure. However, thedisclosure described and claimed herein is not to be limited in scope bythe specific embodiments herein disclosed because these embodiments areintended as illustration of several aspects of the disclosure. Anyequivalent embodiments are intended to be within the scope of thisdisclosure. Indeed, various modifications of the disclosure in additionto those shown and described herein will become apparent to thoseskilled in the art from the foregoing description, which do not departfrom the spirit or scope of the present inventive discovery. Suchmodifications are also intended to fall within the scope of the appendedclaims.

What is claimed is:
 1. A compound of structural Formula III:

or a salt thereof, wherein: n is 4; each R^(X) and R^(Y) isindependently chosen from alkyl, cyano, H, and halo, or two R^(X) groupstogether with the atoms to which they are attached optionally form acycloalkyl ring; A¹ is chosen from C and N; A², A³, and A⁴, areindependently chosen from N, O, S, and CH, wherein at least one of A¹,A², A³, and A⁴ is chosen from N, O, and S; Z¹ is C; Z², Z³ and Z⁴ areindependently chosen from N and CH, wherein at least one of Z¹, Z², Z³,and Z⁴ is N; R¹ and R² are each independently chosen from alkenyl,alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, andheterocycloalkylalkyl, wherein R¹ and R² each may be optionallysubstituted with one to three R^(Z) groups, wherein R¹ and R² togetherwith the atoms to which they are attached optionally form an heteroaryl,or heterocycloalkyl ring, which may be optionally substituted with oneto three R^(Z) groups; R³ is chosen from alkenyl, alkoxy, alkyl, aryl,arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,hydroxyl, C(R⁴)₂C(O)R⁴, C(R⁴)₂C(O)N(R⁴)₂, C(R⁴)₂N(R⁴)₂, C(R⁴)₂NR⁴C(O)R⁴,C(R⁴)₂NR⁴C(O)OR⁴, C(R⁴)₂NR⁴C(O)N(R⁴)₂, C(R⁴)₂NR⁴S(O)R⁴,C(R⁴)₂NR⁴S(O)₂R⁴, N(R⁴)₂, NR⁴C(O)R⁴, NR⁴C(O)OR⁴, NR⁴C(O)N(R⁴)₂,NR⁴S(O)R⁴, NR⁴S(O)₂R⁴, C(O)N(R⁴)₂, S(O)N(R⁴)₂, S(O)₂N(R⁴)₂, C(O)R⁴, SR⁴,S(O)R⁴, and S(O)₂R⁴; wherein each R³ may be optionally substituted withone to three R^(Z) groups; each R⁴ is independently chosen from alkenyl,alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H,halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,heterocycloalkylalkyl, and hydroxyl, wherein each R⁴ may be optionallysubstituted with one to three R^(Z) groups, wherein two R⁴ groupstogether with the atoms to which they are attached optionally form anheteroaryl, or heterocycloalkyl ring, which may be optionallysubstituted with one to three R^(Z) groups; each R^(Z) group isindependently chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl,alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl,alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl,alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl,alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl,alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl,aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano,cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylhaloalkyl,cycloalkyloxy, H, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl,haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl,haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl,haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl,haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl,haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl,haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl,haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl,halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy,haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl,haloheterocycloalkylalkyloxy, haloheterocycloalkyloxy, heteroaryl,heteroarylalkyl, heteroarylalkyloxy, heteroarylhaloalkyl, heteroaryloxy,heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy,heterocycloalkylhaloalkyl, heterocycloalkyloxy, hydroxyl, oxo, N(R⁵)₂,NR⁵C(O)R⁵, NR⁵C(O)OR⁵, NR⁵C(O)N(R⁵)₂, NR⁵S(O)R⁵, NR⁵S(O)₂R⁵, C(O)N(R⁵)₂,S(O)N(R⁵)₂, S(O)₂N(R⁵)₂, C(O)R⁵, C(O)OR⁵, SR⁵, S(O)R⁵, and S(O)₂R⁵; eachR⁵ is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl,cyano, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, whereintwo R⁵ groups together with the atoms to which they are attachedoptionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkylring, which may be optionally substituted with one to three R^(X)groups; and R⁶ is chosen from, alkyl, cyano, cycloalkyl, H, halo,haloalkyl, and heterocycloalkyl, wherein R³ and R⁶ groups together withthe atoms to which they are attached optionally form an aryl,cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may beoptionally substituted with one to three R^(Z) groups.
 2. The compoundas recited in claim 1, or a salt thereof, wherein: A¹ is C; A² and A³are N; and A⁴ is S.
 3. The compound as recited in claim 1, or a saltthereof, wherein: A¹, A², and A³ are N; and A⁴ is CH.
 4. The compound asrecited in claim 1, or a salt thereof, wherein: each R^(X) and R^(Y) isindependently chosen from H and fluoro.
 5. The compound as recited inclaim 1, or a salt thereof, wherein: one of R^(X) is independentlyfluoro.
 6. The compound as recited in claim 1, or a salt thereof,wherein: R¹ is methyl; R² is H.
 7. The compound as recited in claim 1,or a salt thereof, wherein: R¹ is methyl; R² is H; and one of R^(X) isindependently fluoro.
 8. The compound as recited in claim 1, or a saltthereof, wherein: Z² and Z³ are N; Z⁴ is CH; R³ is chosen from N(R⁴)₂,NR⁴C(O)R⁴, NR⁴C(O)OR⁴, and NR⁴C(O)N(R⁴)₂; and R⁶ is H.
 9. The compoundas recited in claim 1, or a salt thereof, wherein: A¹ is C; A² and A³are N; A⁴ is S; n is 4; Z² and Z³ are N; Z⁴ is CH; R³ is chosen fromN(R⁴)₂, NR⁴C(O)R⁴, NR⁴C(O)OR⁴, and NR⁴C(O)N(R⁴)₂; and R⁶ is H.
 10. Thecompound as recited in claim 1, or a salt thereof, wherein: A¹, A², andA³ are N; A⁴ is CH; n is 4; Z² and Z³ are N; Z⁴ is CH; R³ is chosen fromN(R⁴)₂, NR⁴C(O)R⁴, NR⁴C(O)OR⁴, and NR⁴C(O)N(R⁴)₂; and R⁶ is H.
 11. Acompound chosen from

or a salt thereof.